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Showing posts with label microglia. Show all posts
Showing posts with label microglia. Show all posts

Wednesday 23 October 2019

GABAa receptor trafficking, Migraine, Pain, Light Sensitivity, Autophagy, Jacobsen Syndrome, Angelman Syndrome, GABARAP, TRPV1, PX-RICS, CaMKII and CGRP ... Oh and the "fever effect"



The mechanism controlling transporting just the “right” number of GABAA receptors


Today’s post is not for the faint-hearted.  It is another one that could just keep on rolling.  Ling will like it.

It again shows that GABAA receptors are at the centre of much autism, whether single gene or idiopathic. Today we highlight what can go wrong as these receptors are “transported”.

Today’s post also draws on several quite recent papers. It seeks to tie together some previous things mentioned in this blog like the symptoms of pain, particularly felt in the head, sensory sensitivity with dysfunction processes like autophagy and linking it all back to the GABAA receptor.  There is even a link at the end to the "fever effect", which occurs when a high temperature in some people causes a marked improvement in their autism symptoms.

We will come across some expensive drugs like Erenumab, the medical food PEA (Palmitoylethanolamide) and indeed Natasa’s favourite, CBD (Cannabidiol) and a newcomer CBDV (Cannabidivarin).   
We come across a protein called GABARAP (GABAA receptor associated protein) for the first time in this blog.  There is a vast amount in this blog about the GABAA receptor, how and why to modulate it. 

CaMKII makes an appearance, this is a protein kinase that is miss-regulated in much neurological disease. It changes the effect of many other proteins, acting just like a switch, by chemically adding phosphate groups to them. We have previously seen how important the protein kinases PKA, PKB and PKC are to autism.  Today add CaMKII to the list.

We come across another distinctive “face” of autism, this time it is Jacobsen syndrome, which I think is easily spotted by the trained eye, or some facial recognition software.  Jacobsen syndrome is a rare chromosomal disorder resulting from deletion of genes from chromosome 11 that includes band 11q24. This may include the gene that encodes the protein PX-RICS and, if so, it will lead to “autism”. Loss of that gene should be treatable with a GABA agonist.     

We also come back to that happy puppet syndrome (Angelman syndrome) which usually involves loss of the gene UBE3A, from chromosome 15. What I found interesting was that both Jacobsen syndrome and Angelman syndrome should share impaired GABAA receptor trafficking as a feature. They each have a different impediment that should reduce the number of functioning GABAA receptors. In the case of Angelman the impediment is CaMKII inhibition, in Jacobsen it is lack of the protein PX-RICS. Angelman syndrome may well respond to the same therapy as Jacobsen syndrome – a GABA agonist, of just a PAM (positive allosteric modulator, to “turn up the volume”).

Back to GABARAP

GABARAP has multiple functions:

1.     Transport of freshly minted GABAA receptors

In order for newly minted GABAA receptors to get to their final destination it requires four “helpers”: GABARAP, PX-RICS, 14-3-3 and Dynactin.  In addition, you need a dose of CaMKII. If you lack any one of these four, you will end up with reduced expression of GABAA receptors. If CaMKII is overactivated you get too many GABAA receptors.

In Jacobsen Syndrome there is reduced GABAA receptor trafficking/transport, leading to reduced surface expression. (in effect not enough functioning GABAA receptors in situ).  In some people with this syndrome the part of their DNA which encodes PX-RICS is missing.  This lack of PX-RICS produces autism.  The autism-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist.

2.     GABARAP modulates TRPV1 expression

GABARAP also does something totally different, it modulates TRPV1 ion channels, that we have previously touched on in this blog.  This then triggers a cascade of effects relating to pain, neuralgia, migraine headaches, microglial activation, epilepsy and indeed longevity.

The simple function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain. TRPV1 is also known as the capsaicin receptor.  Capsaicin is the active component of chilli peppers.
TRPV1 not only plays a role in pain, but is suggested to play a role in migraine. In migraine TRPV1 plays a role along with calcitonin gene-related peptide receptor (CGRPR). TRPV1 determines how much of the CGRPR protein is produced. CGRPR affects your metabolism broadly and as such plays a key role in longevity.  Ablation of select pain sensory receptors (TRPV1) or the inhibition of CGRP are associated with increased metabolic health and longevity.
Erenumab/Aimovig is a medication which targets CGRPR for the prevention of migraine. It was the first of the group of CGRPR antagonists to be FDA approved in 2018. It is a form of monoclonal antibody therapy in which antibodies are used to block the receptors for the protein CGRP, thought to play a major role in starting migraines.
Recent evidence suggests that TRPV1 may contribute to the onset and progression of some forms of epilepsy;  Cannabidivarin  (CBDV) and cannabidiol (CBD), activate and desensitize TRPV1.
TRPV1 also plays a crucial role in the activation of microglia. As the researchers put it “TRPV1 channels are critical brain inflammation detectorsmicroglia shifted toward an anti-inflammatory phenotype when TRPV1 is lacking.

So, if we jump a few steps forward we can see that desensitizing TRPV1 might be helpful for people with: -

·        Some epilepsy
·        Some neuralgia
·        Perhaps some with chronic migraine
·        People with activated microglia, which is most autism

We also can see that a dysfunction in GABARAP may itself contribute to worsening the above conditions via its effect on TRPV1.


Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. V Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg2+-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.


TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice

The capsaicin receptor TRPV1 has been widely characterized in the sensory system as a key component of pain and inflammation. A large amount of evidence shows that TRPV1 is also functional in the brain although its role is still debated. Here we report that TRPV1 is highly expressed in microglial cells rather than neurons of the anterior cingulate cortex and other brain areas. We found that stimulation of microglial TRPV1 controls cortical microglia activation per se and indirectly enhances glutamatergic transmission in neurons by promoting extracellular microglial microvesicles shedding. Conversely, in the cortex of mice suffering from neuropathic pain, TRPV1 is also present in neurons affecting their intrinsic electrical properties and synaptic strength. Altogether, these findings identify brain TRPV1 as potential detector of harmful stimuli and a key player of microglia to neuron communication.

TRPV1 controls cortical microglia activation

In the healthy mature brain, microglial cells play a role in immune surveillance and ensure the maintenance of brain homeostasis. Upon injuries these cells shift to an activated state characterized by drastic changes in the cellular shape, functional behavior and by the release of different proinflammatory and immunoregulatory factors58,59. Conforming to the capsaicin-mediated induction of microglial chemotaxis29, we investigated whether TRPV1 stimulation regulates the morphology of microglial cells…. Thus, stimulation of TRPV1 induced a pro-inflammatory phenotype of microglia from WTs. Conversely, microglia shifted toward an anti-inflammatory phenotype when TRPV1 is lacking.


Angelman syndrome

Angelman syndrome (Happy puppet syndrome) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, speaking problems, balance and movement problems, seizures, and sleep problems. Children usually have a happy personality and have a particular interest in water. The symptoms generally become noticeable by one year of age.  Angelman syndrome is typically due to a new mutation rather than one inherited from a person's parents. Angelman syndrome is due to a lack of function of part of chromosome 15 inherited from a person's mother. Most of the time, it is due to a deletion or mutation of the UBE3A gene.

CaMKII inhibition underlies Angelman Syndrome



CaMKII
CaMKII is a serine/threonine-specific protein kinase that is regulated by the Ca2+/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+ homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.
Misregulation of CaMKII is linked to Alzheimer’s disease, Angelman syndrome, and heart arrhythmia.

Recent evidence for CaMKII dysregulation in psychiatric diseases is reviewed.
Changes in postsynaptic structure and function appear to be central to multiple diseases.
Altered regulation of the CaMKIIα gene promoter may be a common mechanism among diseases.
CaMKII dysregulation in diverse brain regions may account for myriad disorders.
Although it has been known for decades that hippocampal calcium/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays an essential role in learning and memory consolidation, the roles of CaMKII in other brain regions are only recently being explored in depth. A series of recent studies suggest that CaMKII dysfunction throughout the brain may underlie myriad neuropsychiatric disorders, including drug addiction, schizophrenia, depression, epilepsy, and multiple neurodevelopmental disorders, perhaps through maladaptations in glutamate signaling and neuroplasticity. I review here the structure, function, subcellular localization, and expression patterns of CaMKII isoforms, as well as recent advances demonstrating that disturbances in these properties may contribute to psychiatric disorders.

A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors


Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.
SIGNIFICANCE STATEMENT Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.

Jacobsen Sydrome

The signs and symptoms of Jacobsen syndrome can vary. Most affected people have delayed development of motor skills and speech; cognitive impairment; and learning difficulties. Behavioral features have been reported and may include compulsive behavior; a short attention span; and distractibility. Many people with the condition are diagnosed with attention deficit-hyperactivity disorder (ADHD). The vast majority of people with Jacobsen syndrome also have a bleeding disorder called Paris-Trousseau syndrome, which causes abnormal bleeding and easy bruising. 

People with Jacobsen syndrome typically have distinctive facial features, which include small and low-set ears; wide-set eyes (hypertelorism) with droopy eyelids (ptosis); skin folds covering the inner corner of the eyes; a broad nasal bridge; down-turned corners of the mouth; a thin upper lip; and a small lower jaw (micrognathia). Affected people often have a large head (macrocephaly) and a skull abnormality called trigonocephaly, giving the forehead a pointed appearance.

The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice


GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)–dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABAARs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABAAR transport driven during NMDAR–dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABAARs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS–deficient neurons. This increase in surface GABAARs required the PX-RICS/GABARAP/14–3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII–dependent phosphorylation of PX-RICS to promote PX-RICS–14-3-3 assembly. Notably, PX-RICS/RICS–deficient mice showed impaired amygdala–dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS–mediated GABAAR trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism.

There is a growing consensus that autism arises from the atypical regulation of the excitation/inhibition balance within specific neural microcircuitry. In terms of neural inhibition, autism is closely related to dysfunctional inhibitory signaling mediated by the γ-aminobutyric acid (GABA) type A receptors (GABAARs). Impaired presynaptic release of GABA and postsynaptic trafficking of GABAARs lead to autistic-like social behavior in mouse models of autism. There is a significant reduction in the number of GABAARs and GABAergic activity in certain brain areas of autistic individuals. Genetic association studies have revealed that several GABAAR subunits are linked to an increased risk for autism. GABAAR–mediated signaling is thus essential for the proper regulation of the excitation/inhibition balance associated with socio-emotional cognition.

PX-RICS, GABARAP and 14-3-3ζ/θ are localized in the specific dendritic compartments that are immunopositive for organelle markers for the endoplasmic reticulum (ER), ER exit sites and the trans-Golgi network. This structure, termed the dendritic satellite secretory pathway, is comprised of the dendritic ER and the Golgi outposts and is involved in the local synthesis, processing and transport of membrane-integral or secretory proteins in dendrites. The rapid increase in surface-expressed GABAARs after NMDA stimulation could be explained by the localization of the PX-RICS–dependent trafficking machinery in the dendritic secretory compartments.
Several lines of evidence suggest that the dysregulation of GABA signaling underlies atypical social behavior in autism However, there has been no report describing deficits in GABAergic plasticity that contribute to autistic features. The present study has shown that PX-RICS is essential for GABAergic iLTP and that loss of the PX-RICS function in mice leads to impaired cued fear learning. Cued fear learning is closely associated with GABAAR–mediated activity and plasticity in the amygdala and is inversely correlated with the severity of autistic symptoms. Considering all of these findings, we thus reason that PX-RICS–dependent GABAAR transport may play critical roles in emotional learning in the amygdala through the control of GABAergic synaptic plasticity and that the impairment of this transport mechanism may lead to improper socio-emotional processing, resulting in autistic-like atypical social behavior (Supplementary Fig. 7). Further elucidation of the functional link between GABAergic plasticity and socio-emotional learning could lead to a better understanding of autism pathogenesis and treatment. 
We have previously identified and characterized two splicing isoforms of GTPase-activating proteins specific for Cdc42 predominantly expressed in neurons of the cerebral cortex, amygdala and hippocampus: RICS (ARHGAP32 isoform 2) and PX-RICS (ARHGAP32 isoform 1) . RICS regulates NMDAR–mediated signaling at the postsynaptic density and axonal elongation at the growth cone. In contrast, PX-RICS forms an adaptor complex with GABARAP and 14-3-3ζ/θ to facilitate steady-state trafficking of the N-cadherin/β-catenin complex and GABAARs. PX-RICS is also responsible for autistic-like features observed in more than half of the patients with Jacobsen syndrome (JBS) [3]. Mice lacking PX-RICS/RICS show marked decreases in surface-expressed GABAARs and GABAAR–mediated inhibitory synaptic transmission, resulting in various autistic-like behaviors and autism-related comorbidities. Rare single-nucleotide variations in PX-RICS are also linked to non-syndromic autism, schizophrenia and alexithymia. These findings strongly suggest that dysfunction of PX-RICS–mediated GABAAR trafficking has severe effects on socio-emotional processing of the brain.
Our previous study described above showed that PX-RICS and other components of the GABAAR trafficking complex are required for constitutive transport of the receptor. In this study, we have focused on the role of PX-RICS in the activity–induced promotion of GABAAR trafficking during iLTP. Here we show that PX-RICS–mediated GABAAR trafficking is also involved in NMDAR activity–dependent trafficking of GABAARs and that PX-RICS is a key target of CaMKII for regulating GABAergic synaptic plasticity. Furthermore, we show that PX-RICS dysfunction in mice leads to impaired amygdala–dependent emotional learning, which manifests as autistic-like social behavior [3].




Supplementary Fig. 7. PX-RICS–mediated GABAAR trafficking underlies NMDAR–dependent GABAergic iLTP PX-RICS, GABARAP and 14-3-3s are assembled to form an adaptor complex that interconnects γ2-containing GABAARs (cargo) and dynein/dynactin (motor). Interaction
of PX-RICS with 14-3-3s depends on the phosphorylation activity of CaMKII, and this interaction is a critical regulatory point for GABAAR trafficking. When CaMKII activity is at a basal level, the PX-RICS–mediated trafficking complex has a role in steady-state transport of GABAARs to maintain the number of surface GABAARs as needed for proper synaptic inhibition.3 Neural activity that evokes moderate Ca2+ influx through NMDAR preferentially increases the activated form of CaMKII and elicits its translocation to inhibitory synapses, where it phosphorylates target proteins such as gephyrin and the GABAAR β3 subunit. Phosphorylated gephyrin and the GABAAR β3 subunit regulate the surface dynamics of GABAARs such as lateral diffusion and synaptic confinement. The present study has revealed that PXRICS
is a downstream CaMKII target associated with anterograde transport of
GABAARs. Enhanced PX-RICS phosphorylation increases the PX-RICS–14-3-3 complex and thereby drives de novo GABAAR surface expression, resulting in GABAergic iLTP. Dysfunction of this trafficking mechanism in the amygdala causes impaired GABAergic synaptic plasticity, which may contribute to deficits in socioemotional behavior as observed in PX-RICS/RICS–deficient mice and JBS patients with autism.


PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking


Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.


TRPV1

We now come back to TRPV1, which we saw is modulated by GABARAP.

GABAA receptor associated protein (GABARAP) modulates TRPV1 expression and channel function and desensitization


Transient receptor potential vanilloid (TRPV1) transduces noxious chemical and physical stimuli in high-threshold nociceptors. The pivotal role of TRPV1 in the physiopathology of pain transduction has thrust the identification and characterization of interacting partners that modulate its cellular function. Here, we report that TRPV1 associates with γ-amino butyric acid A-type (GABAA) receptor associated protein (GABARAP) in HEK293 cells and in neurons from dorsal root ganglia coexpressing both proteins. At variance with controls, GABARAP augmented TRPV1 expression in cotransfected cells and stimulated surface receptor clustering. Functionally, GABARAP expression attenuated voltage and capsaicin sensitivity of TRPV1 in the presence of extracellular calcium. Furthermore, the presence of the anchor protein GABARAP notably lengthened the kinetics of vanilloid-induced tachyphylaxia. Notably, the presence of GABARAP selectively increased the interaction of tubulin with the C-terminal domain of TRPV1. Disruption of tubulin cytoskeleton with nocodazole reduced capsaicin-evoked currents in cells expressing TRPV1 and GABARAP, without affecting the kinetics of vanilloid-induced desensitization. Taken together, these findings indicate that GABARAP is an important component of the TRPV1 signaling complex that contributes to increase the channel expression, to traffic and cluster it on the plasma membrane, and to modulate its functional activity at the level of channel gating and desensitization.

‘Entourage’ effectsof N‐palmitoylethanolamide and N‐oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors



Age-Dependent Anti-seizure and Neuroprotective Effect of Cannabidivarin in Neonatal Rats


Neonatal seizures and seizures of infancy represent a significant cause of morbidity. 30–40% of infants and children with seizures will fail to achieve seizure remission with current anti-epileptic drug (AED) treatment. Moreover, pharmacotherapy during critical periods of brain development can adversely affect nervous system function. We, and others, have shown that early life exposure to AEDs including phenobarbital, phenytoin, and valproate are associated with induction of enhanced neuronal apoptosis during a confined period of postnatal development in rats. Thus, identification of new therapies for neonatal/infantile epilepsy syndromes that provide seizure control without neuronal toxicity is a high priority.
Current clinical trials report that modulation of the cannabinoid system with the phytocannabinoid cannabidiol exerts anti-seizure effects in children with epilepsy. While cannabidiol and the propyl analog cannabidivarin (CBDV) display anti-seizure efficacy in adult animal models of seizures/epilepsy, they remained unexplored in neonatal models. Therefore, we investigated the therapeutic potential of CBDV in multiple neonatal rodent seizure models. To evaluate the therapeutic potential of CBDV, we tested its anti-seizure efficacy in five models of neonatal seizures: pentylenetetrazole (PTZ), DMCM, hypoxia, kainate and NMDA-evoked spasms, each representing a different clinical seizure phenotype. We also evaluated the preclinical safety profile in the developing brain.
Postnatal day (P) 10 or P20 male, Sprague-Dawley rat pups were pretreated with CBDV or vehicle prior to chemically or hypoxia induced seizures. CBDV only displayed anticonvulsant effects in the P20 rat pups in the PTZ and DMCM models, with no effect on seizure severity or latency in the P10 animals. Therefore, we next measured the relative expression of known targets for CBDV (TRPV1, TRPA1) to determine a mechanism for which CBDV is anticonvulsant in P20, but not P10 animals. The P20 animals show increased expression of TRPV1 in key brain regions implicated in epileptogenic activity.
Together, these results indicate that modulation of the cannabinoid system in a receptor independent manner can provide seizure control in developing animals, but in an age specific manner. Further, during a developmentally sensitive neonatal period, drugs targeting the cannabinoid system do not induce neuronal apoptosis characteristic of many other AEDs. These results provide some of the first systemic, preclinical data evaluating CBDV in pediatric models of epilepsy.


Weight-based dosing of 10 mg/kg/day of CBDV for 12 weeks
Primary Outcome Measures  :
1.     Aberrant Behavior Checklist-Irritability Subscale (ABC-I) [ Time Frame: Change in ABC-I from Baseline to Week 12 (Change over 12 weeks) ]
Change in ABC-I from Baseline to Endpoint


  

Lack of Autophagy will reduce the number of GABAA receptors, by blocking GABARAP function

Regular readers will recall that one feature of autism and many other neurological diseases is a reduction in autophagy, which I likened to an intra-cellular garbage collection service. 

The very recent paper below shows that lack of autophagy blocks GABARAP from its job to transport freshly minted GABAA receptors.
If correct, this actually has very wide implications.



The disruption of MTOR-regulated macroautophagy/autophagy was previously shown to cause autistic-like abnormalities; however, the underlying molecular defects remained largely unresolved. In a recent study, we demonstrated that autophagy deficiency induced by conditional Atg7 deletion in either forebrain GABAergic inhibitory or excitatory neurons leads to a similar set of autistic-like behavioral abnormalities even when induced following the peak period of synaptic pruning during postnatal neurodevelopment. Our proteomic analysis and molecular dissection further revealed a mechanism in which the GABAA receptor trafficking function of GABARAP (gamma-aminobutyric acid receptor associated protein) family proteins was compromised as they became sequestered by SQSTM1/p62-positive aggregates formed due to autophagy deficiency. Our discovery of autophagy as a link between MTOR and GABA signaling may have implications not limited to neurodevelopmental and neuropsychiatric disorders, but could potentially be involved in other human pathologies such as cancer and diabetes in which both pathways are implicated.


Conclusion

You may have skipped to the conclusion to avoid all the science.

The conclusion is simple, you need to keep your GABAA receptors in tip top form if you want to avoid the symptoms of autism.

o   You need the right number of them
o   You need the right balance among the five constituent subunits
o   You need the correct level of chloride inside neurons so the receptors are not “working backwards”

All of the genes that encode proteins involved in the above are individually “autism genes”, because any one of them can disrupt the process.

Whether it is Dravet syndrome (GABAA receptor α2 subunit), Angelman syndrome, Jacobsen syndrome, Down syndrome or numerous other autism syndromes, not to mention idiopathic autism, check the above 3 bullet points.

Tune up/down your GABAA receptors!

Desensitizing TRPV1 looks interesting and not just for epilepsy.  TRPV1 appears to be essential for microglia in the in brain to be activated.  We know that in autism microglia in the brain are permanently activated, as if there was a threat.

I do think there is cross-talk (feedback loops etc) going on here, for example you can treat the severe epilepsy in Dravet syndrome by any of the following:-

·        KBr, to lower intracellular chloride
·        Low dose clonazepam to affect α subunits of GABAA receptors
·        CBD or CBDV to modify TRPV1


Note that Dravet syndrome is caused by a mutation in the gene that encodes the sodium ion channel Nav1.1, the dysfunction of GABAA receptors is a secondary effect. Also of interest is that the seizures that occur in Dravet syndrome are often triggered by hot temperatures or fever, so you can see how TRPV1 is indeed likely involved.  More generally in idiopathic autism, we have the "fever effect" when high temperatures trigger a reduction in autistic behaviors, making it the opposite of Dravet syndrome. 

On the one hand the biology behind the various problems may look horribly complicated and interwoven, the solutions appear to be much simpler and you have multiple options.

I await the results of the autism clinical trial of CBDV (Cannabidivarin) with interest.

Just impaired autophagy may lead to a reduction in GABAA receptors and the appearance of autistic features in an otherwise “normal” brain. This reminds us again of why autism is not a medical diagnosis, it is just a vague/subjective observation, which, in severe cases, should then trigger a thorough medical investigation.









Thursday 26 September 2019

Treatable Human Endogenous Retroviruses (HERVs) in Multiple Sclerosis (MS), ALS and other Neurological Diseases – an Enemy from Within?



  
A microglial cell, labelled in green, contacts and attacks a myelinated axon (in red). In the presence of the pHERV-W envelope protein, this interaction leads to axonal injury. The blue structures are cell nuclei. Credit: HHU / Joel Gruchot / Patrick Küry
  

It is surprising that only about 2% of human DNA encodes the 20,000 or so genes we all have.  The other 98% used to be called junk DNA.

About 8% of your DNA is made up of Endogenous retroviruses (ERVs) that have been picked up during evolution and most of which have been inactivated and can indeed be regarded as junk. Some of these old viruses that became part of human DNA remain fully functional, can be activated; they are implicated in disease ranging from Multiple Sclerosis (MS), to cancer, to schizophrenia and ALS (motor neuron disease).

The best documented ERV is the one that affects some people with MS, it is called HERV-W  (the H is for Human).  Only in the presence of a protein encoded by this virus can the microglia cells attack the myelin layer on axons.  In this kind of MS, if you could switch off the HERV-W virus you would solve the remyelination problem.

The thing to remember is that MS is a family of conditions and HERV-W may only be relevant to specific sub-types.  The recent research (see below) produced the image at the start of today’s post, where we actually see the microglia (green) mistakenly attacking the healthy myelin on axons (red).

Multiple sclerosis: Endogenous retrovirus HERV-W key to nerve tissue damage


As outlined by first author Dr. David Kremer, the envelope (ENV) protein of the pathogenic human endogenous retrovirus type W (pHERV-W) was found to be a major contributor to nerve damage in MS. In collaboration with research teams in the U.S. and Canada, the authors demonstrated that the ENV protein drives CNS resident microglial cells to contact and damage myelinated axons.                                                                                      



There is a broad repertoire of immunomodulatory drugs that effectively treat the inflammatory aspects of relapsing multiple sclerosis (MS). However, axonal degeneration, which occurs mainly in progressive MS, is still not understood and cannot be treated pharmaceutically. As it is the major factor contributing to clinical disability in MS, it represents an unmet clinical need. A recently completed phase IIb study has demonstrated that anti-pathogenic human endogenous retrovirus type W (pHERV-W) envelope protein (ENV) treatment results in a significant decrease of neurodegenerative brain atrophy in treated MS patients. For these results, the work presented here offers an explanation by demonstrating that, via myeloid cells, pHERV-W ENV directly harms axons.

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.


Relapsing-Remitting Multiple Sclerosis (RRMS)

Most MS starts out as so-called Relapsing-Remitting Multiple Sclerosis (RRMS) and so is the focus of much research. An antibody called GNbAC1 has been developed to specifically target the protein MSRV-Env that is produced by the old human endogenous retrovirus type W.

GNbAC1 for RRMS 

In vitro and in vivo studies showed that GNbAC1 neutralizes MSRV-Env, reducing the inflammatory response and allowing the remyelination repair process to restart.

I think this is an excellent example of how to translate complicated science into a practical therapy.  I just hate to think how much money this therapy will cost.


Or just Antivirals?

I did wonder about a less expensive therapy to block the MSRV-Env protein from activating microglia to destroy myelin.  Why not use a relatively cheap antiviral drug to dampen the virus itself, so it does not make the harmful protein?

Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.

Antiviral drugs normally have to be developed to target a specific virus, but you might just get lucky with an existing drug.

In the case of HIV, a combination of three drugs is used TDF (tenofovir), EFV (efavirenz) and either 3TC (lamivudine) or FTC (emtricitabine).  This therapy has been hugely successful.

The anti-herpes antivirals include valacyclovir (Valtrex), famciclovir (Famvir), and acyclovir (Zovirax).

In the case of Multiple Sclerosis, I did find a study that used acyclovir.  It did not cure the condition, but it did significantly reduce exacerbations.
                                                       






I am afraid nobody seems to want a cheap drug for MS, when the other only partially effective ones can cost $50,000 a year. Acyclovir is much more expensive in the US than elsewhere but nothing like the price of the new MS drugs.

It may of course be a coincidence that Acyclovir reduces exacerbations in MS and may involve an entirely different mechanism.


Human endogenous retroviruses (HERVs) beyond MS

Drugs for MS are a huge business for pharmaceutical companies and this is why the research is advanced.

HERVs have been implicated in ALS (motor neuron disease) and schizophrenia.  There is even some research on HERVs and autism.

It is usually the Herpes virus that gets mentioned in the context of autism. It is probably one of hundreds of possible triggers that, when combined with other “hits” and genetic predispositions, may lead to autism.

Any virus can affect gene expression and so any virus has the potential to cause harm to a developing brain.  This is often all "autism" is, the result of some damage at a critical point in the brain's development. That same event in a teenager does no long term harm. 


Herpes virus may be a trigger for autism

“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus. That idea comports with a body of previous work, like this Swedish study that found that the hospitalization of a woman for any kind of infection during pregnancy increased the risk of the baby developing ASD by 30%.
Some scientists are skeptical that inflammatory molecules alone could be responsible, in part because of the big changes in brain structure that arise in autistic children in the first 2 years of life, just as symptoms of ASD emerge. For instance, a study published in Nature last week documents abnormal overgrowth of the surface of the brain in 6- to 12-month-old babies who go on to be diagnosed with ASD.

Are the 'viral' agents of MS, ALS and schizophrenia buried in our genome?

Viruses hid themselves in your ancestors' DNA; now they're waking up


What if the missing 'environmental' factor in some of our deadliest neurological diseases were really written in our genome? Researchers explain how viruses ended up in our DNA -- and what puts them in the frame in unsolved diseases like multiple sclerosis.

The enemy within
A whopping 8% of our DNA comes from viruses. Specifically, ones called retroviruses -- not because they're old, but because they reverse the normal process of reading DNA to write themselves into their host's genome.
Retroviruses are old though: they began merging with our earliest, primordial ancestors millions of years ago. Over the millennia, most of their remnants in our DNA -- known as human endogenous retroviruses or HERVs -- have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and to this day protect us from infection.
However, HERVs might also be the missing causative link in major 'unsolved' neurological diseases.
"HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]," says senior author Prof. Patrick Kuery. "Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders."

Full paper: -

Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.

Importantly, several studies were able to show that inflammation plays a major role in HERV activation 

SCZ is a complex neuropsychiatric disorder characterized by a variety of cognitive, emotional, and perceptual disturbances. Pathophysiologically, SCZ features decreased brain volume, loss of myelin, and altered astrocyte function (Archer, 2010). In contrast to MS and ALS, both HERV-W and HERV-K have been weakly linked to SCZ based on PCR amplification from CSF and post-mortem brains as well as on protein antigenemia (Yolken et al., 2000Karlsson et al., 2001Frank et al., 2005Perron et al., 2008), while another study revealed upregulation of HERV-W ENV transcripts in plasma samples of SCZ patients (Huang et al., 2011). Moreover, a new study provides evidence that, in early stages of this disease, HERV-K methylation in peripheral blood is reduced (Mak et al., 2019). Of note, these observations contradict an earlier report suggesting that HERV-W expression is reduced in SCZ patients (Weis et al., 2007). The disparity between these reports may reflect different experimental approaches or a differential use of anti-psychotic medications in SCZ patients.

We here present collected evidence that endogenous retroviral elements acting either as viral particles or via their proteins influence neural cells in the context of degenerative CNS diseases. Once thought to be primarily involved in cell transformation (Grabski et al., 2019) and inflammation (Perron and Lang, 2010), emerging data suggests a direct role of these elements in glial and neuronal injury, which in fact goes beyond previous descriptions on the activity of a gliotoxin (Menard et al., 1998). In light of additional observations on the role of ERVs in regulating stem cell potential and fate acquisition (Gautam et al., 2017), the findings describing impacts on committed or mature cells of the CNS are probably not too surprising but warrant future investigations, even more so since neural stem cells are also involved in brain pathology and regeneration. Moreover, the currently still unmet clinical need to effectively treat neurodegeneration necessitates novel therapeutic approaches. Whether similar mechanisms also apply to activation of transposable elements implicated in, for example, chronic fatigue syndrome (CFS; Almenar-Perez et al., 2019) and to what degree currently used neutralizing antibodies can be exploited in order to prevent neural cell activation and/or neurodegeneration needs to be elucidated in the future. In this regard, it remains to be shown whether HERV-employed signaling pathways and epigenetic silencing mechanisms can be used for biomedical translation.



                        

Figure 1 HERV-mediated effects on neural cells. This illustration summarizes origin and observed molecular effects of HERW-W and HERV-K on cells of the central nervous system. Arrow starting points indicate cellular sources of HERV particles or proteins (red dots), whereas arrowheads point to influenced cell types. Modulated processes are shown in gray boxes, and regulated molecules are highlighted in red next to each cell type. The question mark next to TDP-43 refers to its postulated regulation in neurons. Whether microglia and astroglia respond to HERVs in an auto- and/or paracrine way and whether neurons react to internal and/or extracellular HERVs remains to be shown. OPCs: oligodendroglial progenitor cells; NO: nitric oxide; CRP: C-reactive protein; BDNF: brain-derived neurotrophic factor; DRD3: dopamine receptor D3; TRPC3: short transient receptor potential channel 3; DISC1: disrupted in schizophrenia 1; TDP-43: TAR DNA-binding protein 43.
                                  

HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome.






These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer.
Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions.
Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS.
HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases.
These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.
The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

HERVs Expression in Autism Spectrum Disorders

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.



Recent studies suggest that autism spectrum disorders (ASD) result from interactions between genetic and environmental factors, whose possible links could be represented by epigenetic mechanisms. Here, we investigated the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs) from Albanian ASD children, by quantitative real-time PCR. We aimed to confirm the different expression profile already found in Italian ASD children, and to highlight any social and family health condition emerging from information gathered through a questionnaire, to be included among environmental risk factors. The presence of increased HERV-H transcriptional activity in all autistic patients could be understood as a constant epigenetic imprinting of the disease, potentially useful for early diagnosis and for the development of effective novel therapeutic strategies.

Overall, the data obtained in the present study lead us to further support the hypothesis that HERV transcriptional activity is influenced by all the factors mentioned above. Additional work is required to determine if HERV-H expression could be proposed as a biological marker, useful for early detection of children at high risk for ASD, before the appearance of clinical symptoms and for the development of effective new therapeutic strategies. To this end, an in-depth characterization of the potential role of HERV-H in ASD is the major objective of a study currently in progress in murine models. Currently, up to 2% of children worldwide are estimated to be diagnosed with an ASD (Pedersen et al., 2014) and the consistent increment in the prevalence of ASD is considered a pressing challenge for the global public health system. Because children represent more than a third of the Albanian population (Albanian Institute of Statistics 2011) autism is a serious socio-economic problem and its early diagnosis could represent a significant improvement in the treatment of the disease. In fact, if the autistic condition is diagnosed early, a growing repertoire of evidence-based therapies can be applied to give children the best possible chance of life.


Etiotropic and Pathogenetic Therapy of Autism Spectrum Disorder: Case Series of 6 Children


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that reveals itself by social communication problems, restrictive/repetitive behavior, and language impairment. ASD is a growing problem in the USA and in the world with no commonly-accepted etiology resulting in the absence of effective methods of treatment. Based on more than 80 scientific publications we are proposing the following understanding of ASD: it is a genetic disorder, in which some changes in DNA are resulting from a congenital mother to fetus transmitted infection and maternal immune activation. The infections and maternal immune activation result in oxidative stress and production of pro-inflammatory cytokines and other mediators. Based on this understanding, we developed a method of long-term etiotropic and pathogenetic therapy tailored to major chronic/latent infections, inflammation and immune system aberration. We present six cases of ASD treatment, which included the antiviral medication Valacyclovir and five nutritional supplements. The presented results are based on five cycles of treatment continued for 5 months. In all six cases the treatment resulted in social communication skills and behavioral improvements well as positive changes in the physical and psychological conditions. These improvements covariated with a tendency to normalization of blood and immune parameters. Social communication skills, behavioral, physical and psychological improvements also positively affected parents whose subjected quality of life increased over course of the treatment. According to parents of these children, the proposed treatment had superior efficacy compared to other types of treatment that their children underwent before.


Valacyclovir improves cognition in bipolar patients


A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

Anti herpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Objective

To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).

Methods

Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.

Results

Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.

Conclusions

Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.


Conclusion

There is a great deal going on in the world of MS research and if you have MS you might as well consider becoming an early adopter.

As expected, the research on how these old viruses, that should be dormant in our DNA, might play a role in autism is not very advanced.

Some people with autism do take antiviral drugs and I think their caregivers think this relates to a virus they have acquired recently or comes from the mother. Perhaps it is an unidentified virus from that 8% of your DNA that has become activated?

In MS the story is complex but now we know for sure what the virus is, where it came from and what it does. You can defeat it with a tailor-made antibody called GNbAC1 or perhaps just beat it down a little with the common antiviral drug Acyclovir.

Note that antiviral drugs each only have an effect on certain types of virus.

Do HERVs really materially affect some people with autism, and its big brothers bipolar and schizophrenia? There is some limited evidence that they may.

People who report that their children with autism do indeed improve on an antiviral drug are unlikely to ever know which virus was the problem and it may not be the one they thought it was, but it is not a crazy idea.  If it reduces the symptoms of autism without causing troubling side effects, why not?  It is going to work for most autism? Probably not.

For people with Multiple Sclerosis (MS) the science is clear and unambiguous, you need to wipe out the protein called MSRV-Env.

As far as this blog is concerned, we already covered antibiotics in depth.


and today we covered antivirals.  These are the “anti- drugs” that our reader Tanya referred to as not being useful in her case of autism; I think she will be in the majority.  You have to treat your “minority” case of autism, which is what makes it difficult. 

Almost every common autism treatment strategy is misrepresented as a wonder therapy; that is how you sell books, supplements, lab tests and even now I see expensive "training" courses. The reality is somewhat messy and less convenient, but if you read the science great progress does seem to be possible in many cases.