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Title: The molecular basis of activity-dependent somatosensory cortex development
Author: Deighton, Ruth Fiona
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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The murine primary somatosensory cortex (S1) contains discrete cytoarchitectonic units in layer IV called “barrels” that accurately recapitulate the pattern of the mystacial whisker follicles on the facepad. Mice that lack Adenylyl Cyclase 1 (AC1/Adcy1), a Ca2+/calmodulin sensitive adenylyl cyclase that can be regulated by 5HT1b, mGluR and NMDA receptors are “barreless”, lacking both TCA and cellular segregation in layer 4. Adcyl-/- (barreless) mutants also have deficits in LTP/LTD at TCA/layer4 synapses and decreased GluR phosphorylation and association with the PSD. These results led to the hypothesis that LTP/LTD type synaptic plasticity may be required for barrel development. cAMP-dependent Protein Kinase A (PKA) is a major downstream target of AC1, implicating a possible role for PKA in barrel development. I show that while barrels are present in Prkar2β-/- mice, they show significantly reduced cell density ratio between barrel walls and barrel hollows compared to wild-type animals, but normal thalamocortical afferent segregation in the posteromedial barrel subfield. Data clearly show a role for postsynaptic PKA signalling pathways in barrel development and suggest that PKA may not be the principle target downstream of cAMP generated by. Furthermore Prkar2β-/- mice show a defect in GluRA insertion into the PSD of developing TCA synapses, however GluRA, GluRB and GluRC KO mice develop normal barrels, indicating that this process is not necessary for barrel formation. These data suggest that mechanisms of synaptic plasticity can be dissociated from barrel formation. Syngap-/- mice display defects in barreloid segregation in VpM and only partial segregation of TCAs in layer IV into rows rather than whisker-related patches; layer IV neurons fail to segregate into barrels. Syngap+/- mice however display normal barreloid development and TCA segregation, but barrel soma show reduced segregation compared to WT controls. SynGAP is not expressed in brainstem and is not required for barrelette development. In layer 4, SynGAP is selectively expressed I dendrites and postsynaptic densities (PSDs). SynGAP associates with the PSD in a PSD95-indepndent manner. Chapter 5 describes research designed to further elucidate the glutamatergic pathways and cellular processes downstream of PKAR2β – and SynGAP- mediated barrel formation. Preliminary results demonstrate that PKAR2β and SynGAP regulate ERK upon glutamate receptor stimulation. A number of phosphorylation sites are regulated in Prkar2β-/- mice and bioinformatics is helping to identify kinases that act at these sites. A list of genes that are regulated in Prkar2β-/- mice has been identified and is providing a useful tool for focussing future research into the molecular mechanisms of somatosensory cortical development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available