Genes 2 Brains 2 Mind 2 Me

One of the mental functions many of us take for granted is memory – that is – until we’re at the grocery store.  If you’re like me, you dart out of the house confident that you don’t need a list since you’re just going to “pick up a few things” – only to return home and discover (hours later when you’re comfortably ensconced on the couch) that you forgot the ice cream.  Damn, why can’t I have a more efficient working memory system ?  What’s the matter with my lateral frontal cortex ?  Can I (should I) blame it on my genes ? What genes specifically ?

One group recently reported the use of the so-called BOLD-response (blood oxygen level dependent) as a means to sift through the human genome and identify genes that mediate the level of brain activity in the lateral frontal cortex that occur during a working memory task – somewhat akin to remembering a list of groceries.  Steven Potkin and associates in their paper, “Gene discovery through imaging-genetics: identification of two novel genes associated with schizophrenia” [doi: 10.1038/mp.2008.127] examine the level of brain activity in 28 patients with schizophrenia (a disorder where mental function in the lateral frontal cortex is disrupted) and correlate this brain activity (difference between short and long list) with genetic differences at 100,000 snps spread across the autosomes.

They identify 2 genes (that pass an additional series of statistical hurdles designed to weed-out false positive results) RSRC1 and ARHGAP18, heretofore, never having been connected to mental function.  Although neither protein is neuron or brain-specific in its expression, ARHGAP18 is a member of the Rho/Rac/Cdc42-like GTPase activating (RhoGAP) gene family which are well known regulators of the actin cytoskeleton (perhaps  a role in synaptic plasticity ?) and RSRC1 is reported to bind to actin homologs. Also, RSRC1 may play a role in forebrain development since it is expressed in cdc34+ stem cells that migrate under the control of TGF-alpha (As an aside, yours truly co-published a paper showing that TGF-alpha is regulated by early maternal care – possible connection ? Hmm).  A last possibility is a role in RNA splicing which many SR-proteins like RSRC1 function in – which also could be important for synaptic function as many mRNA’s are stored in synaptic terminals.

The authors’ method is completely novel and they seem to have discovered 2 new points from which to further explore the genetic basis of mental disability.  It will be of great interest to see where the research leads next.

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