The genome is just the A,G,T,C bases that encode proteins and other mRNA molecules.  The “epi”genome are various modification to the DNA – such as methylation (at C residues) – and acetylation of histone proteins.   These changes help the DNA form various secondary and tertiary structures that can facilitate or block the interaction of DNA with the transcriptional machinery.

When DNA is highly methylated, it generally is less accessible for transcription and hence gene expression is reduced.  When histone proteins (purple blobs that help DNA coil into a compact shape) are acetylated, the DNA is much more accessible and gene expression goes up.

We know that proper epigenetic regulation is critical for cognitive development because mutations in MeCP2 – a protein that binds to methylated C residues – leads to Rett syndrome.  MeCP2 is normally responsible for binding to methylated DNA and recruiting histone de-acetylases (HDACs) to help DNA coil and condense into a closed form that is inaccessible for gene expression (related post here).

When DNA is accessible for gene expression, then it appears that – during brain development – there are relatively more synaptic spines produced (related post here).  Is this a good thing? Rett syndrome would suggest that – NO – too many synaptic spines and too much excitatory activity during brain development may not be optimal.  Neither is too little excitatory (too much inhibitory) activity and too few synaptic spines.  It is likely that you need just the right balance (related post here). Some have argued (here) that autism & schizophrenia are consequences of too many & too few synapses during development.

The sketch above illustrates a theoretical conjecture – not a scenario that has been verified by extensive scientific study. It tries to explain why epigenetic effects can, in practice, be difficult to disentangle from true (changes in the A,G,T,C sequence) genetic effects.  This is because – for one reason – a mother’s experience (extreme stress, malnutrition, chemical toxins) can – based on some evidence – exert an effect on the methylation of her child’s genome.  Keep in mind, that methylation is normal and widespread throughout the genome during development.  However, in this scenario, if the daughter’s behavior or physiology were to be influenced by such methylation, then she could, in theory, when reaching reproductive age, expose her developing child to an environment that leads to altered methylation (shown here of the grandaughter’s genome).  Thus, an epigenetic change would look much like there is a genetic variant being passed from one generation to the next, but such a genetic variant need not exist (related post here, here) – as its an epigenetic phenomenon.  Genes such as BDNF have been the focus of many genetic/epigenetic studies (here, here) – however, much, much more work remains to determine and understand just how much stress/malnutrition/toxin exposure is enough to cause such multi-generational effects.  Disentangling the interaction of genetics with the environment (and its influence on the epigenome) is a complex task, and it is very difficult to prove the conjecture/model above, so be sure to read the literature and popular press on these topics carefully.

What the heck is an “in”sensitive period then?   Well, whereas visual input is clearly a “good thing” for the sensitive period of visual development, perhaps some inputs are “bad” and it may be useful to shield or protect the brain from exposure.  Maybe some environmental inputs are “bad” and one would not want the developing brain to be exposed to them and say, “OK, this (bad stuff) is normal“.  As a parent, I am constantly telling my children that the traffic-filled street is a “bad place” and, like all parents, I would not want my children to think that it was OK to wander into the street.  Clearly, I want my child to recognize the car-filled street as a “bad thing”.

In the developing brain, it turns out that there are some “bad things” that one would NOT like (the brain) to get accustomed to.  Long-term exposure to glucocorticoids is one example – well-known to cause a type of neuronal remodelling in the hippocampus, that is associated with poor cognitive performance (visit Bruce McEwen’s lab at Rockefeller University to learn more about this).  Perhaps an “in”sensitive period – where the brain is insensitive to glucocorticoids – is one way to teach the brain that glucocorticoids are “bad” and DO NOT get too familiar with them (such a period does actually occur during early post-natal mammalian development).  Of course, we do need our brains to mount an acute stress response, if and when, we are being threatened, but it is also very important that the brain learn to TURN-OFF the acute stress response when the threat has passed – an extensive literature on the deleterious effects of chronic exposure to stress bears this out.  Hence, the brain needs to learn to recognize the flow of glucocorticoids as something that needs to be shut down.

OK, so our developing brain needs to learn what/who is “good vs. bad”.  Perhaps sensitive and insensitive periods help to reinforce this learning – and also – to cement learning into the system in a sort of permanent way (I’m really not sure if this is the consensus view, but I’ll try and podcast interview some of the experts here asap).  In any case, in the case of the visual system, it is clear that the lack of visual input during the sensitive period has long lasting consequences.  In the case of the stress response, it is also clear that if there is untoward stress early in development, one can be (somewhat) destined to endure a lifetime of emotional difficulty.  Previous posts here, here, here cover research on behavioral/genomic correlates of early life stress.

Genes meet environment in the epigenome during sensitive and insensitive periods?

As stated at the outset – genes are not destiny.  The DNA cannot encode a system that knows who/what is good vs. bad, but rather can only encode a system of molecular parts that can assemble to learn these contingencies on the fly.  During sensitive periods in the visual system, cells in the visual system are more active and fire more profusely during the sensitive period. This extra firing leads to changes in gene expression in ways that (somewhat) permanently set the connectivity, strength and sensitivity of visual synapses.  The expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections are well-known tagets of activity-induced gene expression.  Hence the environment “interacts” with the genome via neuronal firing which induces gene expression which – in turn – feeds back and modulates neuronal firing.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Similarly, in the stress response system, the environment induces changes in the firing of cells in the hypothalamus which leads (through a series of intermediates) to the release of glucocorticoids.  Genes induced during the firing of hypothalamic cells and by the release of glucocorticoid can modify the organism’s subsequent response to stressful events.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Digging deeper into the mechanism by which neuronal firing induces gene expression, we find an interesting twist.   Certainly there is a well-studied mechanism wherein neuronal firing causes Ca++ release which activates gene expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections – for many decades.  There is another mechanism that can permanently mark certain genes and alter their levels of expression – in a long-lasting manner.  These are so-called epigenetic mechanisms such as DNA methylation and acetylation.  As covered here and here, for instance, Michael Meaney’s lab has shown that DNA CpG methylation of various genes can vary in response to early-life stress and/or maternal care. In some cases, females who were poorly cared for, may, in turn, be rather lousy mothers themselves as a consequence of these epigenetic markings.

A new research article, “Dynamic DNA methylation programs persistent adverse effects of early-life stress” by Chris Murgatroyd and colleagues [doi:10.1038/nn.2436] explores these mechanisms in great detail.  The team explored the expression of the arginine vasopressin (AVP) peptide – a gene which is important for healthy social interaction and social-stress responsivity.  Among many other interesting results, the team reports that early life stress (using a mouse model) leads to lower levels of methylation in the 3rd CpG island which is located downstream in a distal gene-expression-enhancer region.  In short, more early-life stress was correlated with less methylation, more AVP expression which is known to potentiate the release of glucocorticoids (a bad thing).   The team reports that the methyl binding MeCP2 protein, encoded by the gene that underlies Rett syndrome, acts as a repressor of AVP expression – which would normally be a good thing since it would keep AVP levels (and hence glucocorticoid levels) down.  But unfortunately, early-life stress removes the very methyl groups to which MeCP2 binds and also the team reports that parvocelluar neuronal depolarization leads to phosphorylation (on serine residue #438) of MeCP2 – a form of MeCP2 that is less accessible to its targets.  So, in  a manner similar to other examples, early life stress can have long-lasting effects on gene expression via an epigenetic mechanism – and disables an otherwise protective mechanism that would shield the organism from the effects of stress.  Much like in the case of Rett syndrome (as covered here) it seems that when MeCP2 is bound – then it silences gene expression – which would seem to be a good thing when it comes to the case of AVP.

So who puts these epigenetic marks on chromosomes and why?

I’ll try and explore this further in the weeks ahead.  One intriguing idea about why methylation has been co-opted among mammals, has to do with the idea of parent-offspring conflict.  According to David Haig, one of the experts on this topic, males have various incentives to cause their offspring to be large and fast growing, while females have incentive to combat the genomic tricks that males use, and to keep their offspring smaller and more manageable in size.  The literature clearly show that genes that are marked or methylated by fathers (paternally imprinted genes) tend to be growth promoting genes and that maternally imprinted genes tend to be growth inhibitors.  One might imagine that maternally methylated genes might have an impact on maternal care as well.

Lastly, the growth promoting/inhibiting effects of paternal/maternal genes and gene markings is now starting to be discussed somewhat in the context of autism/schizophrenia which have have been associated with synaptic under-/over-growth, respectively.

Building a brain is already tough enough – but to have to do it amidst an eons-old battle between maternal and paternal genomes.  Sheesh!  More on this to come.

So what are these genes that, in the case of Down syndrome, can alter the course of brain development?  Well, it is widely known that individuals with Down syndrome have an extra copy of chromosome 21.  However, the disorder does not necessarily depend on having an extra copy of each and every gene on chromosome 21.   Rare partial trisomies of only 5.4 million base-pairs on 21q22 can produce the same developmental outcomes as the full chromosome trisomy.  Also, it turns out that mice have a large chunk of mouse chromosome 16 that has the very same linear array of genes (synteny) found on human chromosome 21 (see the figure here).  In mice that have an extra copy of about 104 genes, (the Ts65Dn segment above) many of the developmental traits related to brain structure and physiology are observed.  In mice that have an extra copy of about 81 genes, this is also the case (the Ts1Cje segment).

To focus this line of research even further, the recent paper by Belichenko et al., “The “Down Syndrome Critical Region” Is Sufficient in the Mouse Model to Confer Behavioral, Neurophysiological, and Synaptic Phenotypes Characteristic of Down Syndrome” [DOI:10.1523/JNEUROSCI.1547-09.2009]  examine brain structure, physiology and behavior in a line of mice that carry an extra copy of just 33 genes (this is the Ts1Rhr segment seen in the figure above).  Interestingly, these mice display many of the various traits (admittedly mouse versions) that have been associated with Down syndrome – thus greatly narrowing the search from a whole chromosome to a small number of genes.  20 out of 48 Down syndrome-related traits such as enlargement of dendritic spines, reductions of dendritic spines, brain morphology and various behaviors were  observed.  The authors suggest that 2 genes in this Ts1Rhr segment, in particular, look like intriguing candidates.  DYRK1A a gene, that when over-expressed can lead to hippocampal-dependent learning deficits, and KCNJ6, a potassium channel which could readily drive neurons to hyperpolarize if over-expressed.

The team focused on the BDNF gene whose transcription can be initiated from any one of eight promoter sites (I-XIII).  These sites vary in activity depending on the phase of development and/or the tissue or type of cell – all of which make for a complex set of instructions able to turn the BDNF gene on and off in precise developmental and/or tissue-specific ways.  In the case of promoter IV, it appears to be triggered in the cortex in response to Ca++ release that occurs when neurons are firing – a phenomena called, “neuronal activity dependent transcription” – a top example of how the environment can influence gene expression.  Seeing as how BDNF promoter IV is important for this type of environment-induced gene expression, the team asked what happens when you remove this particular promoter?

To do this, the team constructed – keep in mind that these are – mice that contain mutations in several of the Calcium (Ca++) response elements in the promoter IV region.  They introduced point mutations so that the Ca++ sensitive protein CREB could not bind to the promoter and activate gene expression.  OK, so what happens?

Firstly, the team reports that the mutant mice are more or less indistinguishable from controls in appearance, gait, growth rate, brain size and can also reproduce and transmit the mutations.  WOW! Is that one strike AGAINST nurture? The team then shows that BDNF levels are more than 50% reduced in cultured neurons, but that levels of other immediate early genes are NOT affected (as expected).  In living animals, the effects were similar when they asked how much gene expression occurs in the sensory cortex when animals are exposed to light (after an extended period of darkness).  OK, so there are few effects, so far, other than lower levels of nurture-induced BDNF expression – hmmm. Looking more closely however, the team found that the mutant mice generated lower levels of inhibitory neuron activity – as measured by the firing of miniature inhibitory postsynaptic currents.  Follow-on results showed that the total number of inhibitory neurons (parvalbumin and NPY + GABAergic cells) was no different than controls and so it would seem that the activity dependence of BDNF is important for the maintenance of inhibitory synapses.

Hence, the team has found that what “nurture” does (via the BDNF promoter IV in this case) is to exert an effect on the connectivity of inhibitory neurons.  Wow, thanks mother nurture!  Although it may seem like an obscure role for something as important as THE environment, the team points out that the relative balance of excitation-to-inhibition (yin-yang as covered here for Rett syndrome) is crucial for proper cognitive development.

To explore the notion of inhibory/excitation balance further, check out this (TED link) video lecture, where Michael Merzenich describes this imbalance as a “signal-to-noise” problem wherein some children’s brains are rather noisy (due to any number of genetic/environmental reasons – such as, perhaps, poorly maintained inhibitory connections).  This can make it harder to develop and function in life.  Perhaps someday, the genetic/environment research like that of Hong and colleagues will inform the rehabilitative strategies developed by Merzenich.

In previous posts, we have explored some of the basic molecular (de-repression of chromatin structure) and cellular (excess synaptogenesis) consequences of mutations in the MeCP2 gene – a.k.a the gene whose loss of function gives rise to Rett syndrome.  One of the more difficult aspects of understanding how a mutation in a lowly gene can give rise to changes in cognitive function is bridging a conceptual gap between biochemical functions of a gene product — to its effects on neural network structure and dynamics.  Sure, we can readily acknowledge that neural computations underlie our mental life and that these neurons are simply cells that link-up in special ways – but just what is it about the “connecting up part” that goes wrong during developmental disorders?

In a recent paper entitled, “Intact Long-Term Potentiation but Reduced Connectivity between Neocortical Layer 5 Pyramidal Neurons in a Mouse Model of Rett Syndrome” [doi: 10.1523/jneurosci.1019-09.2009] Vardhan Dani and Sacha Nelson explore this question in great detail.  They address the question by directly measuring the strength of neural connections between pyramidal cells in the somatosensory cortex of healthy and MeCP2 mutant mice.  In earlier reports, MeCP2 neurons showed weaker neurotransmission and weaker plasticity (an ability to change the strength of interconnection – often estimated by a property known as “long term potentiation” (LTP – see video)).   In this paper, the authors examined the connectivity of cortical cells using an electrophysiological method known as patch clamp recording and found that early in development, the LTP induction was comparable in healthy and MeCP2 mutant animals, and even so once the animals were old enough to show cognitive symptoms.  During these early stages of development, there were also no differences between baseline neurotransmission between cortical cells in normal and MeCP2 mice.  Hmmm – no differences? Yes, during the early stages of development, there were no differences between genetic groups – however – once the team examined later stages of development (4 weeks of age) it was apparent that the MeCP2 animals had weaker amplitudes of cortical-cortical excitatory neurotransmission.  Closer comparisons of when the baseline and LTP deficits occurred, suggested that the LTP deficits are secondary to baseline strength of neurotransmission and connectivity in the developing cortex in MeCP2 animals.

So it seems that MeCP2 can alter the excitatory connection strength of cortical cells.  In the discussion of the paper, the authors point out the importance of a proper balance of inhibition and excitation (yin and yang, if you will) in the construction or “connecting up part” of neural networks.  Just as Rett syndrome may arise due to such a problem in the proper linking-up of cells – who use their excitatory and inhibitory connections to establish balanced feedback loops – so too may other developmental disorders such as autism, Down’s syndrome, fragile X-linked mental retardation arise from an improper balance of inhibition and excitation.

With this in mind, I really enjoyed the recent paper “Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions” [doi:10.1523/jneurosci.0324-09.2009] by Maezawa and colleagues.  The authors point out several critical gaps in the literature – namely that the expression of MeCP2 (the gene that, when mutated, gives rise to Rett syndrome) in neurons does NOT account for all of the many facets of the syndrome.  For example, when MeCP2 is deleted only in neurons (in a mouse model), it results in a milder form of abnormal neural development than when deleted in all CNS cell types ( the full mouse syndrome: stereotypic forelimb motions, tremor, motor and social behavioral abnormalities, seizures, hypoactivity, anxiety-like behavior and learning/memory deficits).  Also, it is not possible to reverse or rescue these deficits when a functional version of MeCP2 is expressed under a neuron-specific promoter.  However, when re-expressed under its endogenous promoter – it is possible to rescue the syndrome (free access article).

The authors thus looked much more closely at the expression of MeCP2 and found that they could indeed visualize the expression of the MeCP2 protein in cultured ASTROCYTES – who are a very, very important type of support cell (just think of the personal secretary Lloyd to Ari Gold on the TV show “Entourage”).  The team then examined how astrocytes that lack 80% of the expression of MeCP2 might interact with neurons – the very cells they normally support with secretions of growth factors and cytokines.   It turns out that both normal and MeCP2-deficient neurons do not thrive when co-cultured with astrocytes that have weak MeCP2 expression.   The team reports that dendritic length is reduced after a day and also a fews days of co-culture,  suggesting that the MeCP2-deficient astrocytes are failing to provide the proper trophic support for their neuronal celebrity counterparts.  Short dendrites are generally considered a bad-thing since this would predict poorer connectivity, and poorer cognition across the brain.

Hence, it seems that the lowly astrocyte is far more important in understanding what goes wrong in Rett syndrome.  Ironically, in this case however, the celebrity status of the neuron remains untarnished as astrocytes can now be blamed for the consequences of MeCP2 mutations.  The authors suggest that treatment of Rett syndrome via astrocytes is a worthwhile avenue of investigation.  This new direction in the search for a cure will be an exciting story to follow!

The cognitive and emotional impairments in the autism spectrum disorders can be difficult for parents and siblings to understand and cope with.  Here are some graphics and videos that might assist in understanding how genetic mutations and epigenetic modifications can lead to various forms of social withdrawl commonly observed in the autism spectrum disorders in children.

In this post, the focus is just on the MecP2 gene – where mutations are known to give rise to Rett Syndrome – one of the autism spectrum disorders.  I’ll try and lay out some of the key steps in the typical bare-bones-link-infested-blogger-fashion – starting with mutations in the MecP2 gene.  Disclaimer: there are several fuzzy areas and leaps of faith in the points and mouse model evidence below, and there are many other genes associated with various aspects of autism spectrum disorders that may or may not work in this fashion.  Nevertheless, still it seems one can begin to pull a mechanistic thread from gene to social behavior Stay tuned for more on this topic.

1. The MecP2 gene encodes a protein that binds to 5-Methylcytosine – very simply – a regular cytosine reside with an extra methyl group added at position 5.  Look at the extra -CH3 group on the cytosine residue in the picture at right.  See?  That’s a 5-methylcyctosine residue – and it pairs in the DNA double helix with guanosine (G) in the same fashion as does the regular cyctosine reside (C). OK, now, mutations in the gene that encode the  MecP2 gene – such as those found at Arginine residue 133 and Serine residue 134 impair the ability of the protein to bind to these 5-Methylcyctosine residues.  The figure at left illustrates this, and shows how the MecP2 protein lines up with the bulky yellow 5-Methylcytosine residues in the blue DNA double helix during binding.

2. When the MecP2 protein is bound to the methylated DNA, it serves as a binding site for another type of protein – an HDAC or histone deacetylase. The binding of MecP2 and HDAC (and other proteins (see p172 section 5.3 of this online book “Chromatin Structure and Gene Expression“)).  The binding of the eponymously named HDAC’s leads to the “de-acetylation” of proteins known as histones.  The movie below illustrates how histone “de-acetylation” leads to the condensation of DNA structure and repression or shutting down of gene expression (when the DNA is tightly coiled, it is inaccessible to transcription factors).  Hence: DNA methylation leads (via MecP2, HDAC binding) to a repression on gene expression.

3. When mutated forms of MecP2 cannot bind, the net result is MORE acetylation and MORE gene expression. As covered previously here, this may not be a good thing during brain development since more gene expression can induce the formation of more synapses and – possibly – lead to neural networks that fail to grow and mature in the “normal” fashion. The figure at right suggests that neural networks with too many synapses may not be appropriately connected and may be locked-in to sub-optimal architectures.  Evidence for excessive synaptogenesis is abundant within the autism spectrum disorders.  Neuroligins – a class of genes that have been implicated in autism are known to function in cell & synaptic adhesion (open access review here), and can alter the balance of excitation/inhibition when mutated – which seems consistent with this heuristic model of neural networks that can be too adhesive or sticky.

4. Cognitive and social impairment can result from poor-functioning neural networks containing, but not limited to the amygdala. The normal development of neural networks containing the forntal cortex and amygdala are important for proper social and emotional function.  The last piece of the puzzle then would be to find evidence for developmental abnormalities in these networks and to show that such abnormalities mediate social and/or emotional function.  Such evidence is abundant.

Regarding the effects of MecP2 however, we can consider the work of Adachi et al., who were able to delete the MecP2 gene – just in the amygdala – of (albeit, an adult) mouse.  Doing so, led to the disruption of various emotional behaviors – BUT NOT – of various social interaction deficits that are observed when MecP2 is deleted in the entire forebrain.  This was the case also when the team infused HDAC inhibitors into the amygdala suggesting that loss of transcriptional repression in the adult amygdala may underlie the emotional impariments seen in some autism spectrum disorders.  Hence, such emotional impairments (anxiety etc.) might be treatable in adults (more on this result later and its implications for gene-therapy).

Whew!  Admittedly, the more you know – the more you don’t know.  True here, but still amazing to see the literature starting to interlink across human-genetic, mouse-genetic, human-functional-imaging levels of analysis. Hoping this rambling was helpful.

The homunculus (argument) is a pesky problem in cognitive science – a little guy who might suddenly appear when you propose a mechanism for decision making, spontaneous action or forethought  etc. – and would take credit for the origination of the neural impulse.  While there are many mechanistic models of decision making that have slain the little bugger – by invoking competition between past experience and memory as the source of new thoughts and ideas – one must always tread lightly, I suppose, to be wary that cognitive mechanisms are based completely in neural properties devoid of a homuncular source.

Still, the human mind must begin somewhere.  After all, its just a ball of cells initially, and then a tube and then some more folds, layers, neurogenesis and neural migration  etc. before maturing – miraculously – into a child that one day looks at you and says, “momma” or “dada”.  How do these neural networks come into being?  Who or what guides their development toward that unforgettable, “momma (dada)” moment?  A somewhat homuncluar “genetic program” – whose instructions we can attribute to millions of years of natural selection?  Did early hominid babies say “momma (dada)?  Hmmm. Seems like we might be placing a lot of faith in the so-called “instructions” provided by the genome, but who am I to quibble.

On the other hand, you might find that the recent paper by Akhtar et al., “Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function” [doi:10.1523/jneurosci.0097-09.2009] may change the way you think about cognitive development.  The team explores the function of two very important epigenetic regulators of gene expression – histone deacetylases 1,2 (HDAC1, HDAC2) on the functionality of synapses in early developing mice and mature animals.  By epigenetic, I refer to the role of these genes in regulating chromatin structure and not via direct, site-specific DNA binding.  The way the HDAC genes work is by de-acetylating – removing acetyl groups – thus removing a electrostatic repulsion of acetyl groups (negative charge) on histone proteins with the phosphate backbone of DNA (also a negative charge).  When the histone proteins carry such an acetyl group, they do NOT bind well to DNA (negative-negative charge repulsion) and the DNA molecule is more open and exposed to binding of transcription factors that activate gene expression.  Thus if one (as Akhtar do) turns off a de-acetylating HDAC gene, then the resulting animal has a genome that is more open and exposed to transcription factor binding and gene expression.  Less HDAC = more gene expression!

What were the effects on synaptic function?  To summarize, the team found that in early development (neonatal mouse hippocampal cells) cells where the HDAC1 or 2 genes were turned off (either through pharmacologic blockers or via partial deletion of the gene(s) via lentivirus introduction of Cre recombinase) had more synapses and more synaptic electrical activity than did hippocampal cells from control animals.  Keep in mind that the HDACs are located in the nucleus of the neuron and the synapses are far, far away.  Amazingly – they are under the control of an epigenetic regulator of gene expression;  hence, ahem, “epigenetic puppetmasters”.  In adult cells, the knockdown of HDACs did not show the same effects on synaptic formation and activity.  Rather the cells where HDAC2 was shut down showed less synaptic formation and activity (HDAC1 had no effect).  Again, it is amazing to see effects on synaptic function regulated at vast distances.  Neat!

The authors suggest that the epigenetic regulatory system of HDAC1 & 2 can serve to regulate the overall levels of synaptic formation during early cognitive development.  If I understand their comments in the discussion, this may be because, you don’t necessarily want to have too many active synapses during the formation of a neural network.   Might such networks might be prone to excitotoxic damage or perhaps to being locked-in to inefficient circuits?  The authors note that HDACs interact with MecP2, a gene associated with Rett Syndrome – a developmental disorder (in many ways similar to autism) where neural networks underlying cognitive development in children fail to progress to support higher, more flexible forms of cognition.  Surely the results of Akhtar et al., must be a key to understanding and treating these disorders.

Interestingly, here, the controller of these developmental phenotypes is not a “genetic program” but rather an epigenetic one, whose effects are wide-spread across the genome and heavily influenced by the environment.  So no need for an homunculus here.

With this premise in mind, it is fascinating to ponder some recent findings reported by Huffaker et al. in their research article, “A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia” [doi: 10.1038/nm.1962].  Here, the research team has identified a gene, KCNH2, that is both differentially expressed in brains of schizophrenia patients vs. healthy controls and that contains several SNP genetic variants (rs3800779, rs748693, rs1036145) that are associated with multiple different patient populations.  Furthermore, the team finds that the risk-associated SNPs are associated with greater expression of an isoform of KCNH2 – a kind of special isoform – one that is expressed in humans and other primates, but not in rodents (they show a frame-shift nucleotide change that renders their ATG start codon out of frame and their copy non-expressed).  Last I checked, primates and rodents shared a common ancestor many millenia ago. Very neat – since some have suggested that newer evolutionary innovations might still have some kinks that need to be worked out.

In any case, the research team shows that the 3 SNPs are associated with a variety of brain parameters such as hippocampal volume, hippocampal activity (declarative memory task) and activity in the dorsolateral prefrontal cortex (DLPFC). The main suggestion of how these variants in KCNH2 might lead to these brain changes and risk for schizophrenia comes from previous findings that mutations in this gene screw up the efflux of K+ ions during the repolarization phase of an action potential.  In the heart (where KCNH2 is also expressed) this has been shown to lead to a form of “long QT syndrome“.  Thus, the team explores this idea using primary neuronal cell cultures and confirms that greater expression of the primate isoform leads to non-adaptive, quickly deactivating, faster firing patterns, presumably due to the extra K+ channels. 

The authors hint that fast & extended spiking is – in the context of human cognition – is thought to be a good thing since its needed to allow the binding of multiple input streams.  However, in this case, the variants seem to have pushed the process to a non-adaptive extreme.  Perhaps there is a seed of an interesting evolutionary story here, since the innovation (longer, extended firing in the DLPFC) that allows humans to ponder so many ideas at the same time, may have some legacy non-adaptive genetic variation still floating around in the human lineage.  Just a speculative muse – but fun to consider in a blog post.

In any case, the team has substantiated a very plausible mechanism for how the genetic variants may give rise to the disorder.  A scientific tour-de-force if there ever was one.

On a personal note, I checked my 23andMe profile and found that while rs3800779 and rs748693 were not assayed, rs1036145 was, and I – boringly – am a middling G/A heterozygote.  In this article, the researchers find that the A/As showed smaller right-hippocampal grey matter volume, but the G/A were not different that the G/Gs.  During a declarative memory task, the GGs showed little or no change in hippocampal activity while the AA and GA group showed changes – but only in the left hippocampus.  In the N-back task (a working memory task), the AA’s showed more changes in brain activation in the right DLPFC compared to the GGs and GAs.

For further edification, here is a video showing the structure of the KCNH2-type K+ channel.  Marvel at the tiny pore that allows red K+ ions to leak through during the repolarization phase of an action potential.   **PODCAST accompanies this post**