Posted in Cerebellum, CNTNAP2, Frontal cortex, Frontal pole, Fusiform gyrus, Rostral fronto-occipital fasciculus, Thalamus, White matter, tagged 23andMe, Add new tag, autism, Autism spectrum, Brain, Development, Frontal lobe, Functional magnetic resonance imaging, Genetic testing, Genetics, Grey matter, Health, Mental disorder, Mental health, Neural development, Neurodevelopmental, synaptogenesis, White matter on March 5, 2010|
Leave a Comment »
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.
Read Full Post »
Posted in FMR1, Somatosensory cortex, Thalamus, tagged autism, Autism spectrum, Brain, Cognition, critical period, Development, Mental disorder, Mutation, pruning, Rett Syndrome, sensory overload, synaptic plasticity, synaptic pruning on February 13, 2010|
Leave a Comment »
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.
Read Full Post »
Posted in BDNF, MECP2, tagged Anxiety, Art, autism, Cognition, cognitive development, Development, Epigenetics, Gene, Gene expression, MECP2, meme-art, Rett Syndrome, schizophrenia, Stress, synaptogenesis, Transcription on December 16, 2009|
2 Comments »
Some quick sketches that might help put the fast-growing epigenetics and cognitive development literature into context. Visit the University of Utah’s Epigenetics training site for more background!
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.
Read Full Post »
Posted in Chromosome structural variants, Intronic or repetitive sequences, tagged autism, Autism spectrum, Cognition, Genetic testing, Mental disorder, Mental health, Neural development, Neurodevelopmental, schizophrenia on December 7, 2009|
1 Comment »
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.
Read Full Post »
Posted in Chromosome structural variants, tagged autism, Bipolar disorder, Brain, Development, DNA, Gene expression, Mental disorder, Mental health, Mood, schizophrenia on October 27, 2009|
1 Comment »
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.
Read Full Post »
While most presentations at SfN cover brief snippets of research, yesterday it was a delight to hear the story of neurexins and neuroligins – the whole, decades worth of research, story – from Professor Thomas Sudhof, whose lab has been responsible for the purification and biochemical characterization of these proteins. Without re-telling the tale here, a few neat highlights about these proteins who form a transynaptic bridge with neurexins on the pre-synaptic membrane binding to neuroligins on the post-synaptic membrane:
-neurexins were first purified using alpha-latrotoxin (a.k.a black widow venom!)
-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.
Read Full Post »