Genes 2 Brains 2 Mind 2 Me

Hey, why should neurons get all the adulation – you know – like an organization with 40,000 members complete with an annual fest in exotic locales?  After all, glial cells outnumber neurons many-fold and a single astrocyte can ensheath and support many hundreds of neurons.  Perhaps it may be that who gets top billing may not be so much an issue of who is more important, but just a matter of who is better known (its who you know in life that matters right?).

These were my thoughts at the start of Professor Ben A. Barres’ talk, “What do Glial Cells Do?” which I greatly enjoyed today.  One of the key things glia do, it turns out, is to help neurons form new synapses.  This can be shown by culturing astrocytes and then applying the conditioned media to rat ganglion cells – who respond by making new postsynaptic densities and also increasing the externalization of AMPA receptors.  The mediator of this process was identified as thrombospondin – a molecule that is secreted by astrocytes and binds, via its EDF-repeat domain, to a neurally expressed molecule known as alpha-2-delta-1 calcium channel subunit which signals in an integrin-like manner to initiate the formation of excitatory synapses.  A few other highlights from the talk were:

-thrombospondin is the gene which is MOST upregulated in expression when human vs. monkey brain mRNA levels are compared.

-the synapse-inducing effects of astrocytes work only in immature astrocytes and injured/reactive astrocytes, but not mature ones.

-overexpression of the alpha-2-delta-1 calcium channel subunit can induce synapse formation.

-some medications such as gabapentin/neurontin bind to the alpha-2-delta-1 calcium channel subunit and can actually interfere with the new synapse formation – red flagging these meds for use during pregnancy and in children

-there is a metal-binding domain in alpha-2-delta-1 calcium channel subunit which may – possibly – be a target for lead binding and be a reason for why small amounts of exposure to lead can lead to mental retardation

Another highlight of the talk was Professor Barres brief personal comments on the importance of gender and cultural diversity in the practice of science. I was impressed by his warm and supportive remarks to students who may be concerned about diversity and discrimination in the field of science.  Check out his wikipedia page for more.

Todays session, “Synaptic Receptor and Regulation” has been a wonderful overview of a great diversity of synaptic components.  Across the talks, it is abundantly clear that synaptic proteins – particularly those located in the post-synaptic density (PSD) are over-represented in mental and developmental disorders.  Hence, it is clear that understanding how these proteins work will help understand brain-related illness.  Another common theme is that most of the proteins discussed so far seem to interact via a common latticework of proteins such as PSD95 and gephrin which are prone to polymerize in ways that provide a scaffold for ion channels and other receptors that intitiate action potentials.  Hence, it seems that 3-D structure IS function when talking about synapses.  Just a smattering of highlights for me were:

-amazing 3-D tomographic reconstructions of the PSD

-protein palmitoylation is necessary for proper spine formation (perhaps because ras & rho use such modifications during signalling?)

-that a conformational change in collybistin upon binding with neuroligins is what promotes the clustering of ion channels

-a failure to stabilize AMPA receptors is an underlying cause of mental retardation

-the localization of synapses in the axon initial segment is regulated by neurofascin – which is expressed just there in that very tiny aspect of a neuron!

-beautiful 3-D reconstructions of dentrites, spines and astrocytes entwined together and also detailed freeze-fracture replica images of AMPA receptor localization (clustered in the center of the active zone) and NMDA channels (more diffusely spaced)

-the dishevelled gene (the mouse knockout has a behavioral phenotype) regulates AcH receptor localization in c. elegans.

-red hot chilli pepper spice (a.k.a. capsaicin) is actually able to cause AMPA receptors to internalize and depress neural activity.

-the PSD is highly conserved in vertebrates and has very ancient evolutionary roots as far back as our common ancestor with yeast! yet the most divergent genes are those involved in neural development.

-still trying to figure out what “the calyx of held” is … more on that later … blasted wifi here

Happened to snap this pic of Thomas Insel, Director of NIMH this morning.  I couldn’t help wonder what he might have been thinking.

“Sheese, my institute pays a bundle for this, and even I can’t find a bite to eat?”

Just wondering.

Should I take the shuttle bus or the Metra?  Should I go to the big lecture or the smaller talk?  Do I eat McD’s on level 2 or do I head off-site and take my chances?  Lately it seems, these are the really big questions – in addition to the usual ones about how brains work and how they give rise to minds.  But just what’s going on under the hood when you are weighing your options (McD’s vs. off-site eating turns out to be a false choice or Hobson’s choice as I discovered today)?

A number of fantastic insights were offered at today’s session on Basic Decision-Making Mechanisms.  These speakers were fond of systems-level analyses and seemed most interested in patterns of brain activity that are correlated with performance on decision-making tasks.  Not surprisingly, there are a number of such correlates, many, it seems, residing in the lateral and medial frontal cortex.  What do these correlates do? and how, exactly, do they function to help me make the right decisions (sadly, this would be McD’s). J.T. McGuire from Princeton University showed interesting patterns of activity in ventral temporal lobes and suggested that one interpretation of these correlates was that frontal networks are regulators of circuits that carry out earlier stages of processing.  P. Stiers from Maastricht University showed that there are a common set of frontal brain areas that co-activate across several executive function and decision-making tasks – and also that these regions show high functional connectivity regardless of tasks.  Perhaps this suggests a pre-wired neural network – or at least a consortia of networks – as one question from the audience pointed out.  In some individuals, lesions can impair decision-making and C. Azuar from the Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, La Pitié Salpêtrière Hospital in Paris revealed that these lesions tend to reside in the same frontal areas that are activated when healthy volunteers perform decision-making tasks – a finding that supports the  “cascade model” of decision-making.  Lastly, I enjoyed the presentation by J.J. Yoo of MIT who asked if real-time analysis of brain activations can be used to influence decisions or at least facilitate better memory of scenes.  Are there brain states that predict better memory encoding?  Her team focused the parahippocampal place area, where higher activity had been associated with better memory encoding, and then presented stimuli to subjects only when they were in a “good” brain state  vs. “bad” brain state.  This manipulation improved recall from 15% when in the “bad state” up to 22% recall when stimuli were presented to subjects when they were in the “good state”. Wow! Mind reading is for real.

Just think, at SfN 2029, we can have our brains scanned BEFORE deciding where to go for lunch!