One of the longstanding puzzles of brain development is why, in some cases, individuals with developmental disabilities sometimes show enhanced function, rather than a more typical loss of cognitive function.  In the case of Williams Syndrome – which is caused by a hemizygous deletion of a cluster of about 25 genes on 7q11.23 – children show a mild form of mental retardation but also a notable increase in gregarious and social behavior.  How might a genetic deletion lead to a gain of function ? In a recent paper by Sarpal and colleagues [doi:10.1093/cercor/bhn004], they explore the role of the visual cortex and its role in feeding and filtering information to emotional  regions of the brain.

From its receipt of visual information from the eyes – say perhaps, you’re looking at someone’s face, the primary visual cortex parses information into 2 separate streams – a dorsal stream which is good at processing “where” information related to location; and a ventral stream which is good at processing “what”information related to identity and recognition – and moreover, provides inputs to the prefrontal and amygdala (brain regions which are important for social behaviors). What if the genes deleted in Williams Syndrome altered the development of a part of visual cortex that participates in early visual processing to alter the relative balance of dorsal to ventral processing ?  Might it result in a an individual who was better than usual at processing objects (faces) and also showing related emotional traits ? Indeed, this has been a longstanding hypothesis that has since been supported by findings that show relatively intact ventral stream processing but disrupted dorsal stream processing.

In their current paper, Sarpal and colleagues measured brain activity as well as correlations of activity (connectivity) between brain regions as patients with WS passively viewed visual objects (faces and houses).  They report that connections from early visual processing areas (fusiform and parahippocampal gyrus) in WS are actually weaker to the frontal cortex and amygdala.  Since activation of the frontal cortex and amygdala are associated with inhibition and fear, it may be case that the weaker connections from early visual areas to these regions gives rise to the type of gregarious and prosocial (a lack of fear and inhibition) behavior seen in WS.   In further pinpointing where in the brain the genes for WS might be causing a developmental change, the authors point to the ventral lip of the collateral sulcus, an area situated between the fusiform and parahippocampal gyri.  This may be the spot to more closely examine the role of genes such as LIMK1 – a gene that participates in the function of the actin cytoskeleton (an important process in synaptic formation).

This lecture by V.S. Ramachandran covers some of these pathways with respect to Capgras Syndrome.

Image by lintmachine via Flickr

Like “Joe the Plumber” (whose real name is Samuel), CNTNAP2 (whose real name is CASPR2) has achieved a bit of fame lately.  While recently appearing almost everywhere (here, here, here) except FOX News, CNTNAP2 (not Joe the Plumber) is apparently a transcriptional target of the infamous FOXP2 “language gene” – so says Sonja C. Vernes & colleagues [doi: 10.1056/NEJMoa0802828] who precipitated DNA-protein complexes using anti-FOXP2 antibodies from a cell line transiently expressing FOXP2. The team later evaluated measures of expressive and receptive language abilities and nonsense-word repetition and found that a series of snps – most significantly rs17236239 – were associated with performance of children from a consortium of families at risk for language impairment.  This adds to several previous reports of CNTNAP2 and risk for autism, a disorder where language ability is severely impaired.

So what’s all the fuss ? How can something so insignificant (rs17236239 not Joe the Plumber) stir up so much trouble ?  Well, as reported in a previous post, the expression of CNTNAP2 in the developing superior temporal cortex may be a relevant clue since this brain region is activated by language tasks.  Also, this gene encodes a rather massive protein which (as reported by Coman et al.,) seems to participate in the establishment of myelination and “nodes” that permit rapid neural transmission and long-range coordination across neural structures in the brain. Interestingly, this gene shows evidence for recent positive selection in humans (as posted on here and here) although the newly derived G-allele at rs17236239 seems to be the allele that is causing the language difficulties.  My own 23andMe profile shows a middling A/G here which makes it slightly hard to recall and repeat “Samuel Wurzelbacher”.

Image via Wikipedia

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The acquisition of language in humans remains a complex and fascinating mystery from both a neuro- and evolutionary-biological perspective. Attempts to identify genetic regulators of neural processes that are involved in language acquisition have the potential to shed light, not only on the natural history of homo sapiens, but also, to help understand the complex neurodevelopmental disorder, Autism, often associated with profound language impairments. So, it is very exciting to read, “Genome-wide analyses of human perisylvian cerebral cortical patterning” by Abrahams et al., (DOI) who examined human gene expression in frontal vs. superior temporal cortex at a developmental period where neurogenesis and neuronal migration are particularly active. The authors went looking for differential gene expression during a critical developmental time point and in a critical brain region – since the superior temporal cortex is an area that is reliably activated by linguistic tasks as well as social cognition tasks. According to the article, a total of 345 differentially expressed genes were identified, with 61 enriched and 284 down-regulated in superior temporal cortex across two microarray platforms, with 13 genes identified by both microarray array platforms. One of the genes identified is LDB1, a regulator of the asymmetrically expressed LIM domain-only 4 (LMO4) a known mediator of calcium-dependent transcription in cortical neurons and known to regulate thalamocortical connectivity. Another gene, CNTNAP2, a member of the neurexin transmembrane superfamily of proteins that mediate cellular interactions in the nervous system has been previously associated with autism. Both of these genes seem to have important developmental roles and should provide access to the fine-scale wiring that occurs during the development of neural networks involved in language.

Comparisons of human genome variation within and across closely related species have great potential to reveal ways in which the brain and mind of modern humans may or may not have differed from our hominid ancestors. Such comparisons have recently revealed a great many genomic targets of natural selection, some of which are expressed in the developing brain, and, hence, might provide clues to the mental life of our ancestors. Variation in two such candidates ASPM (rs964201) and MCPH1 (rs2442496) arose approximately 50,000 years ago and show strong positive selection in the lineage leading to humans. What do these genes and common variants do ? Do they affect language acquisition ? Social behavior ? Intelligence ? Any type of process that might smack of something uniquely ‘human’ ? In their paper [DOI], “Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort“, Dobson-Stone et al., used structural MRI to determine whether differences in whole brain volume or grey matter volume might relate to either or both of these variants. Although no evidence was found that relate these common variants (rare mutations can cause microcephaly) their methodological approach seems like a fantastic strategy for gaining insights into our human origins.