Perugia is an ancient university city in Central Italy. If you live in North America you may recall it in connection with a high profile murder trial. You probably would not expect it to produce clever insights into autism.
In fact, Italy is a rare country outside the US that has leading autism researchers.
Today’s post is to draw your attention to very insightful paper about some of the ion channel dysfunctions in autism. This paper is about those concerning potassium.
The nice touch was their suggestion that we could classify some people with ASD, some with epilepsy and some people with both, by their ion channel dysfunction.
So if like some people, you have a dysfunction of the L-type calcium channel Cav1.2, you would become:-
Cav1.2-channelASD
Somebody with Dravet Syndrome (epilepsy) with ASD, would become:-
Nav1.1channelASD-channelepsy
The underlying assumption by the authors is that a type of single ion channel dysfunction, generally triggered by the underlying gene being dysfunctional, and may account for many cases of “autism”.
This is interesting, but I tend to believe that multiple ion channel dysfunctions (channelopathies) are present and in some cases the underlying gene itself is not the problem. Ion channels and transporters are proteins and each type is indeed expressed by its gene, but the degree to which that gene is expressed is also determined by many other factors. So over/under expression of, for example, an ion transporter might well not correspond to any genetic error.
We have already seen that in addition to ion channels there are also various types of ion transporter/exchangers. Two very important ones in autism are NKCC1 and KCC2, they determine the chloride concentration within brain cells. Too many NKCC1 transporters and/or too few KCC2 transporters mean that the level of chloride is too high. This then causes an ongoing dysfunction of the neurotransmitter GABA. So in this case the route problem is not a dysfunction of the transporter rather there are just too many of them.
NKCC1 is also expressed in many regions of the brain during early development, but not in adulthood.[5] This change in NKCC1 presence seems to be responsible for altering responses to the neurotransmitters GABA and glycine from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as NKCC1 transporters are predominantly active, internal chloride concentrations in neurons is raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, outward driving force for this ions increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential for chloride, given by the Nernst equation. Later in development expression of NKCC1 is reduced, while expression of a KCC2 K-Cl cotransporter increased, thus bringing internal chloride concentration in neurons down to adult values
So we could call this common autism phenotype NKCC1 over expression.
Then the type of autism I am interested in would become:-
Cav1.2-channelASD with NKCC1 over expression
This assumes that no potassium or sodium channels are affected.
Back to Potassium Ion Channelopathies
Here is the paper from Perugia:-
Here is the paper from Perugia:-
.. a mounting body of evidence indicates that ion channel dysfunction may well enhance autism susceptibility also when other contributing alleles are coinherited.
Direct and indirect defects in K+ channels have been implicated in ASDs pathogenesis, likely altering crucial neural network processes in several brain areas including the cerebellum, a structure that emerges as critically involved in determining the core features of ASDs. Abnormal synaptic transmission and dendritic spine pathology play crucial roles in ASDs. Notably, the activity of many thousands synapses is controlled by a single astrocyte. Thus, aberrant astrocyte dependent synaptic functions and CNS development, induced by defective ion channels, represent an interesting causative hypotheses for ASDs
Kv4.2 – ChannelASD
The presence of Kv4.2 channels in hippocampus appears fundamental, mostly at early developmental stage when neuronal activity drives synaptic maturation and network refinement. At hippocampal synapses, the gradual reduction in GluN2B/GluN2A subunit ratio, during post-natal development, is correlated with AMPA expression and synaptic maturation. Ablation of Kv4.2 in mice abolished this phenomenon and resulted in a higher number of silent synapses in the adulthood. Given the importance of Kv4.2 in brain development and functioning, defects of this channel have been unsurprisingly correlated with a broad spectrum of neurological disorders. Gene deletion in mice leads to increased susceptibility to convulsant stimuli and truncating mutation of Kv4.2 in humans leads to temporal lobe epilepsy
Kv4.2 channel expression may also participate in establishing the conditions for the development of ASDs, given that Kv4.2 mRNA can bind to the fragile X mental retardation protein (FMRP), which is associated to fragile X syndrome (FXS), the most common monogenic cause of autism and inherited intellectual retardation
Kv7.3 – ChannelASD
KCNQ3 and KCNQ2 gene mutations segregate with various forms of Kv7.3/Kv7.2-channelepsies
KCa1.1 – ChannelASD
The calcium-activated K+ 230 (KCa) channels are highly conserved across species, and widely expressed in the human brain.
KCa1.1 loss-of function mutations likely alter pyramidal neurons excitability and result in impairment of neural networks in hippocampus, an area implicated in cognition, mood disorders and ASD. However, these mutations may also affect cerebellar PNs excitability, development, learning and memory processes, suggesting that KCa1.1 channels dysfunction may impact these crucial neurophysiological processes occurring within the cerebellum and result in the psychomotor development and cognition features of ASD
Recently, KCa1.1 channels have been implicated in ASD on a different ground, since their activity is regulated by FMRP, whose mutation produces FXS.
Notably, FMRP can also bind to Na+-activated K+ channel Slack (i.e. KCa4.1), and thus regulate its activity.
Interestingly, intellectual disability only occurs in those patients who carry mutations in Slack channels, further suggesting a role for this channel type in both epilepsy and cognitive disorders
Inwardly-rectifying K+ channels
Inwardly-rectifying K+ (Kir) channels take their name from the greater conductance at potentials negative to EK, while at more positive values the outward flow of K+ ions is variably inhibited by cytoplasmic polyamines and Mg2+, by means of affinity dependent blockade
Kir2.1 – ChannelASD
Loss-of-function mutations in the KCNJ2 gene are responsible for the rare Andersen-Tawil syndrome a condition characterized by long QT-syndrome, cardiac arrhythmia, skeletal abnormalities, periodic paralysis, mood disorders and seizures
genetically-induced Kir2.1 defects, beside causing SQT3 syndrome, may possibly result in functional impairment of neural networks where this channel type resides and contribute to ASDs pathogenesis
I do think Kir2.1 is interesting because it seems to be related hypokalemic sensory overload, which if a key feature of many people’s ASD and indeed ADHD.
Interestingly, a reader with the above Andersen-Tawil syndrome and relatives with ASD, told me how many of them smoke and feel much better by doing so.
Abstract
Nicotine has been shown to depolarize membrane potential and to lengthen action potential duration in isolated cardiac preparations. To investigate whether this is a consequence of direct interaction of nicotine with inward rectifier K(+) channels which are a key determinant of membrane potentials, we assessed the effects of nicotine on two cloned human inward rectifier K(+) channels, Kir2.1 and Kir2.2, expressed in Xenopus oocytes and the native inward rectifier K(+) current I(K1) in canine ventricular myocytes. Nicotine suppressed Kir2.1-expressed currents at varying potentials negative to -20 mV, with more pronounced effects on the outward current between -70 and -20 mV relative to the inward current at hyperpolarized potentials (below -70 mV). The inhibition was concentration dependent. For the outward currents recorded at -50 mV, the IC50 was 165 +/- 18 microM. Similar effects of nicotine were observed for Kir2.2. A more potent effect was seen with I(K1) in canine myocytes. Significant blockade ( approximately 60%) was found at a concentration as low as 0.5 microM and the IC50 was 4.0 +/- 0.4 microM. The effects in both oocytes and myocytes were partially reversible upon washout of nicotine. Antagonists of nicotinic receptors (mecamylamine, 100 microM), muscarinic receptors (atropine, 1 microM), and beta-adrenergic receptors (propranolol, 1 microM) all failed to restore the depressed currents, suggesting that nicotine acted directly on Kir channels, independent of catecholamine release. This property of nicotine may explain its membrane-depolarizing and action potential duration-prolonging effects in cardiac cells and may contribute in part to its ability to promote propensity for cardiac arrhythmias
Some people with ASD find nicotine patches helpful. This could help for various reasons, but if they are Kir2.1 – ChannelASD, then likely it is blocking the misbehaving potassium channels.
