GABA Neuron Subpopulation and the Regulation of Cortical Neuronal and Behavior

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

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