The overarching goal of Project 4 is to characterize disease-relevant neurophysiological and behavioral phenotypes in two genetic models of developmental interneuronopathies: Cyclin D2 nulls and the Six3- Cre:Smo(FI/FI) conditional nulls of the sonic hedgehog (Shh) pathway developed in Projs. 1 and 2, respectively. Anatomical data provided by Projs 1,2 and 4 and Core B indicate that these two genetic models differ in terms of their impact on MGE-derived interneurons in at least 2 important aspects: 1) relative decreases in parvalbumin-expressing (Pv+) vs. somatostatin-expressing (SSN+) subpopulations and 2) differential effects on neocortical and hippocampal subregions. Specifically, the cyclin D2 model exhibits a loss of Pv+ but not SSN+ interneurons in the cortex;moreover the hippocampus shows a more marked reduction in Pv+ interneurons, relative to neocortical regions. On the other hand, the Six3-Cre:Smo(FI/FI) model shows a loss of both Pv+ and SSN+ interneurons in both neocortex and hippocampus. In Project 4, the impact of these different patterns of interneuron deficits will be determined using a combination of electophysiological, functional-anatomical, and behavioral experiments. Electrophysiological experiments will test the hypothesis that local GABA transmission is reduced in the neocortex and hippocampus of these mutant mice. The behavioral experiments will characterize changes in seizure threshold and fear-related behaviors in response to decreases in efficacy of the GABAA-benzodiazepine receptor. Correlations between behavior and cortical neuron activity will be assessed by telemetry-based EEGs in behaving animals and by quantifying induction patterns of the immediate early gene c-fos following administration of ligands that negatively modulate the GABAA-BZ receptor. Together these studies will characterize the impact of the """"""""maldevelopment"""""""" of specific interneuron subpopulations on the functional postnatal development of prefrontal and limbic cortical circuitry mediating mood regulation (specifically, fear) and seizure susceptibility. Pathological development of interneuron populations of the neocortex and hippocampus are thought to contribute to several developmental brain disorders including seizures, cognitive disabilities, autism and schizophrenia. Preclinical research supports the idea that the affective symptoms and cognitive deficits that often accompany these disorders may also be, in part, mediated by a disruption of cortical GABA transmission or its developmental consequences. Thus Project 4 has broad relevance for epilepsy and disorders of mood and cognition.
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