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Posts Tagged ‘Mouse’

Violinist marionette performs
Image by eugene via Flickr

The homunculus (argument) is a pesky problem in cognitive science – a little guy who might suddenly appear when you propose a mechanism for decision making, spontaneous action or forethought  etc. – and would take credit for the origination of the neural impulse.  While there are many mechanistic models of decision making that have slain the little bugger – by invoking competition between past experience and memory as the source of new thoughts and ideas – one must always tread lightly, I suppose, to be wary that cognitive mechanisms are based completely in neural properties devoid of a homuncular source.

Still, the human mind must begin somewhere.  After all, its just a ball of cells initially, and then a tube and then some more folds, layers, neurogenesis and neural migration  etc. before maturing – miraculously – into a child that one day looks at you and says, “momma” or “dada”.  How do these neural networks come into being?  Who or what guides their development toward that unforgettable, “momma (dada)” moment?  A somewhat homuncluar “genetic program” – whose instructions we can attribute to millions of years of natural selection?  Did early hominid babies say “momma (dada)?  Hmmm. Seems like we might be placing a lot of faith in the so-called “instructions” provided by the genome, but who am I to quibble.

On the other hand, you might find that the recent paper by Akhtar et al., “Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function” [doi:10.1523/jneurosci.0097-09.2009] may change the way you think about cognitive development.  The team explores the function of two very important epigenetic regulators of gene expression – histone deacetylases 1,2 (HDAC1, HDAC2) on the functionality of synapses in early developing mice and mature animals.  By epigenetic, I refer to the role of these genes in regulating chromatin structure and not via direct, site-specific DNA binding.  The way the HDAC genes work is by de-acetylating – removing acetyl groups – thus removing a electrostatic repulsion of acetyl groups (negative charge) on histone proteins with the phosphate backbone of DNA (also a negative charge).  When the histone proteins carry such an acetyl group, they do NOT bind well to DNA (negative-negative charge repulsion) and the DNA molecule is more open and exposed to binding of transcription factors that activate gene expression.  Thus if one (as Akhtar do) turns off a de-acetylating HDAC gene, then the resulting animal has a genome that is more open and exposed to transcription factor binding and gene expression.  Less HDAC = more gene expression!

What were the effects on synaptic function?  To summarize, the team found that in early development (neonatal mouse hippocampal cells) cells where the HDAC1 or 2 genes were turned off (either through pharmacologic blockers or via partial deletion of the gene(s) via lentivirus introduction of Cre recombinase) had more synapses and more synaptic electrical activity than did hippocampal cells from control animals.  Keep in mind that the HDACs are located in the nucleus of the neuron and the synapses are far, far away.  Amazingly – they are under the control of an epigenetic regulator of gene expression;  hence, ahem, “epigenetic puppetmasters”.  In adult cells, the knockdown of HDACs did not show the same effects on synaptic formation and activity.  Rather the cells where HDAC2 was shut down showed less synaptic formation and activity (HDAC1 had no effect).  Again, it is amazing to see effects on synaptic function regulated at vast distances.  Neat!

The authors suggest that the epigenetic regulatory system of HDAC1 & 2 can serve to regulate the overall levels of synaptic formation during early cognitive development.  If I understand their comments in the discussion, this may be because, you don’t necessarily want to have too many active synapses during the formation of a neural network.   Might such networks might be prone to excitotoxic damage or perhaps to being locked-in to inefficient circuits?  The authors note that HDACs interact with MecP2, a gene associated with Rett Syndrome – a developmental disorder (in many ways similar to autism) where neural networks underlying cognitive development in children fail to progress to support higher, more flexible forms of cognition.  Surely the results of Akhtar et al., must be a key to understanding and treating these disorders.

Interestingly, here, the controller of these developmental phenotypes is not a “genetic program” but rather an epigenetic one, whose effects are wide-spread across the genome and heavily influenced by the environment.  So no need for an homunculus here.

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Drawing of Purkinje cells (A) and granule cell...
Image via Wikipedia

If you like gardening, the doldrums of winter can be dreary indeed. Although I’d never admit to it, my neighbors might swear to having seen me outside strangely (pathetically) counting the number of branches on my icicle-laden roses and rhododendrons.  In any case, I do admit to spending way too much time forlornly staring at my garden from the window while fantasizing about all the things I’ll plant come springtime.

Each new branch brings a new burst of color and fragrance and concomitant joy.  A good thing right ?  Similarly, each neuron in the brain – which look just like little trees with branches – should also strive to send out as many new branches and make new synaptic connections.  Afterall, there are brain disorders associated with a loss of or fewer dendrites, such as Down’s syndrome and schizophrenia. More branches, more synapses, more brain power and concomitant joy ? Well, perhaps not quite.

A gene known as seizure-related gene 6 (sez6) which is expressed in the developing brain as well as in response to environmental stimulation, seems to play a role in limiting the the number of branches that a neuron can send out.  Gunnersen and colleagues [doi: 10.1016/j.neuron.2007.09.018] show that mice that carry an inactivated version of sez6 show more dendritic branches (implying that the normal function of the active gene is to inhibit branch formation), and that this is definitely not a good thing.  These sez6(-/-) mice, while looking rather indistinguishable from their normal littermates, did not perform as well on tasks involving motor control, memory and emotional sensitivity (implying that having too many branches may not be so beneficial).  In humans, a frameshift mutation involving an insertion of a C residue at position 1435 of the cDNA is associated with febrile seizures, similarly suggesting that dendritic overload can have negative effects on human brain function.

Clearly, the human brain seeks a balance between too many and too few dendritic branches.  I suppose most experienced gardeners would also agree that too many branches is not desirable.  Perhaps they are right.  However, I don’t think I’d mind much if plants came with an analogous sez6 mutation !

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Drosophila melanogasterImage via Wikipedia Skimming the abstracts in BMC, I was surprised to find that a fruit fly logs a slothful 8-14 hours of sleep per day! Douglas and colleagues in their paper, “Sleep in Kcna2 knockout mice” show that the mouse ortholog of the Drosophila mutation, Shaker (an alpha subunit of a voltage activated potassium channel) that disrupts normal fly sleep, also keeps mice awake at night.

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The DISC1 mouse is a major step forward in a translational research path towards understanding how genes contribute to the risk of complex mental disorders such as schizophrenia. The latest mouse (see PNAS – Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans by Hikida et al.) attempts to replace the normal mouse gene with a human mutation. The deficits parallel human abnormalities in a remarkable way. Note, however, that Joseph Gogos and colleagues (including my one-time boss Maria Karayiorgou) have shown (see PNAS -Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice by Hiroko et al.) that an ostensibly normal mouse inbred strain (normal, that is, if you’re inbred for one, and a mouse, for another) carries a truncated form of DISC1. Both of these mouse models show deficits in frontal cortex dependent behaviors but, together, they also demonstrate how the many interacting genes in the background can modify and ameliorate the effects of a single mutation. Do the genes that modify DISC1 in mice modify risk in humans?

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