The A-to-T SNP rs7794745 in the CNTNAP2 gene was found to be associated with increased risk of autism (see Arking et al., 2008).  Specifically, the TT genotype, found in about 15% of individuals, increases these folks’ risk by about 1.2-1.7-fold.  Sure enough, when I checked my 23andMe profile, I found that I’m one of these TT risk-bearing individuals.  Interesting, although not alarming since me and my kids are beyond the age where one typically worries about autism.  Still, one can wonder if such a risk factor might have exerted some influence on the development of my brain?

The recent paper by Tan et al., “Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2” [doi:10.1016/j.neuroimage.2010.02.018 ] suggests there may be subtle, but still profound influences of the TT genotype on brain development in healthy individuals.  According to the authors, “homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation.”

The FA (fractional anisotropy – a measurement of white-matter or myelination) results are consistent with a role of CNTNAP2 in the establishment of synaptic contacts and other cell-cell contacts especially at Nodes of Ranvier – which are critical for proper function of white-matter tracts that support rapid, long-range neural transmission.  Indeed, more severe mutations in CNTNAP2  have been associated with cortical dysplasia and focal epilepsy (Strauss et al., 2006).

Subtle changes perhaps influencing long-range information flow in my brain – wow!

More on CNTNAP2 … its evolutionary history and role in language development.

If you have a minute, check out this “Autism Sensory Overload Simulation” video to get a feel for the perceptual difficulties experienced by people with autism spectrum disorders.  A recent article, “Critical Period Plasticity Is Disrupted in the Barrel Cortex of Fmr1 Knockout Mice” [doi: 10.1016/j.neuron.2010.01.024] provides some clues to the cellular mechanisms that are involved in this phenomenon.  The authors examined the developing somatosensory cortex in lab mice who carry a mutation in a gene called FMR1.  The normal function of this gene is to help synapses mature and optimize their strength through a process known as activity-dependent plasticity.  This a kind of “use-it-or-lose-it” neural activity that is important when you are practicing and practicing to learn something new – say, like riding a bike, or learning a new language.  Improvements in performance that come from “using” the circuits in the brain are correlated with optimized synaptic connections – via a complex set of biochemical reactions (eg. AMPA receptor trafficking).

When FMR1 is not functioning, neuronal connections (in this case, synapses that connect the thalamus to the somatosensory cortex) cannot mature and develop properly.  This wreaks havoc in the developing brain where maturation can occur in successive critical periods – where the maturation of one circuit is needed to ensure the subsequent development of another.  Hence, the authors suggest, the type of sensory overload reported in the autism spectrum disorders may be related to a similar type of developmental anomaly in the somatosensory cortex.

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.

Other research covered (here, here) demonstrates the importance of the proper balance of excitatory and inhibitory signalling during cortical development.

Nowadays, it seems that genomics is spreading beyond the rarefied realm of science and academia into the general, consumer-based popular culture.  Quelle surprise!?  Yes, the era of the personal genome is close at hand, even as present technology  provides – directly to the general consumer public – a  genome-wide sampling of many hundreds of thousands of single nucleotide variants.   As curious early adopters begin to surf their personal genomic information, one might wonder how they, and  homo sapiens in general, will ultimately utilize their genome information.  Interestingly, some have already adapted the personal genome to facilitate what homo sapiens loves to do most – that is, to interact with one another.  They are at the vanguard of a new and hip form of social interaction known as “personal genome sharing”.  People connecting in cyberspace – via  haplotype or sequence alignment – initiating new social contacts with distant cousins (of which there may be many tens of thousands at 5th cousins and beyond).  Sharing genes that regulate the social interaction of sharing genes, as it were.

A broader view of social genes, within the context of our neo-Darwinian synthesis, however, shows that the relationship between the genome and social behavior can be rather complex.  When genes contribute directly to the fitness of an organism (eg. sharper tooth and claw), it is relatively straightforward to explain how novel fitness-conferring genetic variants increase in frequency from generation to generation.  Even when genetic variants are selfish, that is, when they subvert the recombination or gamete production machinery, in some cases to the detriment of their individual host, they can still readily spread through populations.  However, when a new genetic variant confers a fitness benefit to unrelated individuals by enhancing a cooperative or reciprocally-altruistic form of social interaction, it becomes more difficult to explain how such a novel genetic variant can take hold and spread in a large, randomly mating population.  Debates on the feasibility natural selection acting “above the level of the individual” seem settled against this proposition.  However, even in the face of such difficult population genetic conundrums, research on the psychology, biology and evolutionary genetics of social interactions continues unabated.  Like our primate and other mammalian cousins, with whom homo sapiens shares some 90-99% genetic identity, we are an intensely social species as our literature, poetry, music, cinema, not to mention the more recent twittering, myspacing, facebooking and genome-sharing demonstrate.

Indeed, many of the most compelling examples of genetic research on social interactions are those that reveal the devastating impacts on psychological development and function when social interaction is restricted.  In cases of maternal and/or peer-group social separation stress, the effects on gene expression in the brain are dramatic and lead to long-lasting consequences on human emotional function.  Studies on loneliness by John Cacioppo and colleagues reveal that even the perception of loneliness is aversive enough to raise arousal levels which, may, have adaptive value.  A number of specific genes have been shown to interact with a history of neglect or maltreatment in childhood and, subsequently, increase the risk of depression or emotional lability in adulthood.  Clearly then, despite the difficulties in explaining how new “social genes” arise and take hold in populations, the human genome been shaped over evolutionary time to function optimally within the context of a social group.

From this perspective, a new paper, “Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans” by Sarina Rodrigues and colleagues [doi.org/10.1073/pnas.0909579106] may be of broad interest as a recent addition to a long-standing, but now very rapidly growing, flow of genetic research on genes and social interactions.  The research team explored just a single genetic variant in the gene encoding the receptor for a small neuropeptide known as oxytocin, a protein with well-studied effects on human social interactions.  Intra-nasal administration of oxytocin, for example, has been reported to enhance eye-gaze, trust, generosity and the ability to infer the emotional state of others.  In the Rodrigues et al., study, a silent G to A change (rs53576) within exon 3 of the oxytocin receptor (OXTR) gene is used to subgroup an ethnically diverse population of 192 healthy college students who participated in assessments for pro-social traits such as the “Reading the Mind in the Eyes” (RMET) test of empathetic accuracy as well as measures of dispositional empathy.  Although an appraisal of emotionality in others is not a cooperative behavior per se, it has been demonstrated to be essential for healthy social function.  The Rodrigues et al., team find that the subgroup of students who carried the GG genotype were more accurate and able to discern the emotional state of others than students who carried the A-allele.  Such molecular genetic results are an important branching point to further examine neural and cognitive mechanisms of empathy as well as long-standing population genetic concerns of how new genetic variants like the A-allele of rs53576 arose and managed to take-hold in human populations.

Regarding the latter, there are many avenues for inquiry, but oxytocin’s role in the regulation of the reproductive cycle and social behavior stands out as an ideal target for natural selection.  Reproductive and behavioral-genetic factors that influence the ritualized interactions between males and females have been demonstrated to be targets of natural selection during the process of speciation.  New variants can reduce the cross-mating of closely related species who might otherwise mate and produce sterile or inviable hybrid offspring.  So-called pre-mating speciation mechanisms are an efficient means, therefore, to ensure that reproduction leads to fit and fertile offspring.  In connection with this idea, reports of an eye-gaze assessment similar to the RMET test used by Rodrigues et al., revealed that women’s pupils dilate more widely to photos of men they were sexually attracted to during their period of the menstrual cycle of greatest fertility, thus demonstrating a viable link between social preference and reproductive biology.  However, in the Rodrigues et al., study, it was the G-allele that was associated with superior social appraisal and this allele is not the novel allele, but rather the ancestral allele that is carried by chimpanzees, macaques and orangutans.  Therefore, it does not seem that the novel A-allele would have been targeted by natural selection in this type of pre-mating social-interaction scenrio.  Might other aspects of OXTR function provide more insight then?  Rodrigues et al.,  explore the role of the gene beyond the social interaction dimension and note that OXTR is widely expressed in limbic circuitry and also plays a broader modulatory role in many emotional reactivity.  For this reason, they sought to assess the stress responsivity of the participants via changes in heart-rate that are elicited by the unpredictable onset of an acoustic startle.  The results show that the A-allele carriers showed greater stress reactivity and also greater scores on a 12-point scale of affective reactivity.  Might greater emotional vigilance in the face of adversity confer a fitness advantage for A-allele carriers? Perhaps this could be further explored.

Regarding the neural and cognitive mechanisms of empathy and other pro-social traits, the Rodrigues et al., strategy demonstrates that when human psychological research includes genetic information it can more readily be informed by a wealth of non-human animal models.  Comparisons of genotype-phenotype correlations at the behavioral, physiological, anatomical and cellular levels across different model systems is one general strategy for generating hypotheses about how a gene like OXTR mediates and moderates cognitive function and also why it (and human behavior) evolved.  For example, mice that lack the OXTR gene show higher levels of aggression and deficits in social recognition memory.  In humans, genetic associations of the A-allele with autism, and social loneliness form possible translational bridges.  In other areas of human psychology such as in the areas of attention and inhibition, several genetic variants correlate with specific  mental operations and areas of brain activation.  The psychological construct of inhibition, once debated purely from a behavioral psychological perspective, is now better understood to be carried out by a collection of neural networks that function in the lateral frontal cortex as well as basal ganglia and frontal midline.  Individual differences in the activation of these brain regions have been shown to relate to genetic differences in a number of dopaminergic genes, whose function in animal models is readily linked to the physiologic function of specific neural circuits and types of synapses.  In the area of social psychology, where such types of neuroimaging-genetic studies are just getting underway, the use of “hyper-scanning”, a method that involves the simultaneous neuroimaging of two or more individuals playing a social game (prisoners dilemma) reveals a co-activation of dopamine-rich brain areas when players are able to make sound predictions of other participant’s choices.  These types of social games can model specific aspects of reciprocal social interactions such as trust, punishment, policing, sanctions etc. that have been postulated to support the evolution of social behavior via reciprocal altruism.  Similar imaging work showed that intra-nasal administration of oxytocin potently reduced amygdala activation and decreased amygdala coupling to brainstem regions implicated in autonomic and behavioural manifestations of fear.  Such recent examples affirm the presence of a core neural circuitry involved in social interaction whose anatomical and physiological properties can be probed using genetic methods in human and non-human populations.

Although there will remain complexities in explaining how new “social genes” can arise and move through evolutionary space and time (let alone cyberspace!) the inter-flows of genetic data and social psychological function in homo sapiens will likely increase.  The rising tide should inevitably force both psychologists and evolutionary biologists to break out of long-standing academic silos and work together to construct coherent models that are consistent with cognitive-genetic findings as well as population- genetic and phylogenetic data.  Such efforts will heavily depend on a foundation of psychological research into “social genes” in a manner illustrated by Rodrigues et al.

*** PODCAST accompanies this post *** Thanks agian Dr. Rodrigues!!!

File this story under “the more you know, the more you don’t know” or simply under “WTF!“  The new paper, “Microduplications of 16p11.2 are associated with schizophrenia” [doi:10.1038/ng.474] reveals that a short stretch of DNA on chromosome 16p11.2 is – very rarely – duplicated and – more rarely – deleted.  In an analysis of 8,590 individuals with schizophrenia, 2,172 with developmental delay or autism, 4,822 with bipolar disorder and 30,492 controls, the the microduplication of 16p11.2 was strongly associated with schizophrenia, bipolar and autism while the reciprocal microdeletion was strongly associated with developmental delay or autism – but not associated with schizophrenia or bipolar disorder.

OK, so the title of my post is misleading (hey, its a blog) since there are clearly many additional factors that contribute to the developmental outcome of autism vs. schizophrenia, but this stretch of DNA seems to hold clues about early development of brain systems that go awry in both disorders.  Here is a list of the brain expressed genes in this 600 kbp region (in order from telomere-side to centromere-side): SPN, QPRT, C16orf54, MAZ, PRRT2, C16orf53, MVP, CDIPT, SEZ6L2, ASPHD1, KCTD13, TMEM219, TAOK2, HIRIP3, INO80E, DOC2A, FLJ25404, FAM57B, ALDOA, PPP4C, TBX6, YPEL3, GDPD3, MAPK3, CORO1A.

Any guess as to which one(s) are the culprits?  I’ll go with HIRIP3 given its role in chromatin structure regulation – and the consequent regulation of under- (schiz?)/over- (autism) growth of synapses. What an amazing mystery to pursue.

-there are thousands of spice variants of a single neurexin gene and these have rather specific affinities for different splice variants of neuroligins (how are these splicing events regulated to ensure the right pairs find each other?)

-the mere act of ectopic expression of neuroligins is sufficient induce the formation of synapses in neuronal cell lines – however this will not happen if the neuroligin is missing its neurexin binding domain.  Apparently, different neuroligin genes confer the formation of different types of inhibitory vs. excitatory synapses.

-interestingly, the deletion of any pair of the 3 (NL1,2,3) neuroligin genes has little effect – albeit for a few subtle social behavior phenotypes in mice.  Deletion of all 3 of the NL genes is lethal.

-In humans, mutations in neuroligins such as R87W and R451C are associated with autism spectrum disorder.  Apparently, these mutations do not fold properly and do not make it to the cell surface.

-The R451C mutation, when expressed in a mouse leads to more inhibitory synapses in the cortex and more excitatory synapses in the hippocampus.  The mice are BETTER able to learn/unlearn the water-maze paradigm but show subtle social affiliation phenotypes.

-There are a number of other mutations in genes that interact with the neurexins and neuroligins that are also associated with mental disability, suggesting that the proper regulation of synaptic organization and excitatory/inhibitory balance is a key aspect of optimal mental function.

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.