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Posts Tagged ‘Neural development’

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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.

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The recent paper, “Comparative genomics of autism and schizophrenia” by Bernard Crespi and colleagues provides a very exciting take on how genetic data can be mined to understand cognitive development and mental illness.  Looking at genetic association data for autism and schizophrenia, the authors point out that 4 loci are associated with both schizophrenia and autism – however, with a particular twist.  In the case of 1q21.1 and 22q11.21 it seems that genetic deletions are associated with schizophrenia while duplications at this locus are associated with autism.  At 16p11.2 and 22q13.3  it seems that duplications are associated with schizophrenia and deletions are associated with autism.  Thus both loci contain genes that regulate brain development such that too much (duplication) or too little (deletion) of these genes can cause brain development to go awry.  The authors point to genes involved in cellular and synaptic growth for which loss-of-function in growth inhibition genes (which would cause overgrowth) have been associated with autism while loss-of-function in growth promoting genes (which would cause undergrowth) have been associated with schizophrenia.  Certainly there is much evidence for overproduction of synapses in the autism-spectrum disorders and loss of synapses in schizophrenia.  Crespi et al., [doi:10.1073/pnas.0906080106]

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

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We are all familiar with the notion that genes are NOT destiny and that the development of an individual’s mind and body occur in a manner that is sensitive to the environment (e.g. children who eat lots of healthy food grow bigger and stronger than those who have little or no access to food).  In the case of the brain, one of the ways in which the environment gets factored into development – is via so-called “sensitive periods” where certain parts of the brain transiently rely on sensory experience in order to develop.  Children born with cataracts, for example, will have much better vision if the cataracts are removed in the first few weeks of life rather than later on.  This is because the human visual system has a “sensitive period” early in development where it is extra-sensitive to visual input and, after which, the function and connectivity of various parts of the system is – somewhat permanently – established for the rest of the person’s life.  Hence, if there is little visual input (cataracts) during the sensitive period, then the visual system is somewhat permanently unable to process visual information – even if the cataracts are subsequently removed.  (To learn more about this topic, visit Pawan Sinha’s lab at M.I.T and his Project Prakash intervention study on childhood blindness.)

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.

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SfNneuroblogbadgeIn 13th century India,  the story was originally told of a group of blind men (or men in the dark) who touch an elephant to learn what it is like.  Each one touches a different part, but only one part, such as the side or the tusk.  They then compare notes on what they felt, and learn they are in complete disagreement.

With this ancient story in mind,  I’d like to introduce you to the annual conference of the Society for Neuroscience, or SfN, where brain enthusiasts across the globe gather for 5 days to compare notes – not on an elephant – but on something more massive – the brain and mind.  The vast complexities of neural development and communication will be shared amongst some 31,000+ participants in an effort to integrate findings from molecular to neural physiology to systems dynamics to behavior and find some  agreement on one of the all-time great biological mysteries.

As but a single humble molecular/cognitive/neuro/blogger, I will do my best to focus specifically on stories and highlights that address the dilemma of the bind men and the elephant and look for stories that  interlink different levels of analysis and help integrate data and models across different levels of analysis. I am fascinated by the way in which data from molecular levels of analysis can be interlinked with synaptic and systems levels of analysis and so hope to relate some of these interconnections with my readers.

You can readily follow the action at this years gathering using the fantastic organizational, informatic tools on the SfN meeting planner.  There are a number of resources to support neuro-bloggers and theme-specific neuro-tweeters.  Also, DrugMonkey has a growing list of other SfN tweeters/bloggers.  The real-time flow on Twitter #sfn09 as well as #sfnthemea & (b,c,d,e, and the notorious h) is already amazing !!

Please join the fray and share your thoughts with the SfN community! See you in Chicago.

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arinlloydCelebrities and politicians are known for their love of the spotlight.  “Me, me, me!”  are the words to get ahead by in our modern media circus.   As well, it can even be – in the unglamorous world of science – where, in characteristically geeky form, the conventional wisdom is to shout, “my hypothesis, my hypothesis, my hypothesis!”.  Once, for example, I had a grad school professor say she was not allowed by her department to teach about glial cells in her brain development class.  Another distinguished professor once told me, “don’t even bother sending a grant in,  if it is focused on white matter“.   No sir, it appears that modern neuroscience shall only focus on one main hypothesis – the neuron doctrine and not on the lowly support cells (astrocytes, oligodendrocytes & microglia) that, actually, make up more than 90% of the human brain.  Hmmm, who would have thought to find such a cult of neuronal celebrity in the halls of academia?

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!

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