Wednesday, May 8, 2024
5/8/2024
Summary Inhibitory interneurons in cerebral cortex show rapid plasticity of intrinsic excitability in response to sensory experience and learning. The molecular mechanisms and functions of such plasticity, and its potential role in disease, are poorly understood. We study this in mouse somatosensory cortex (S1), where brief sensory deprivation drives a rapid reduction in parvalbumin (PV) interneuron intrinsic excitability, which acts to stabilize pyramidal cell firing rates. We recently found similar plasticity in somatostatin (SST) interneurons, suggesting that rapid intrinsic plasticity is a common property of MGE-derived interneurons. Here, we characterize the mechanisms for intrinsic plasticity in interneurons, and test the novel hypothesis that deficits in this process play a major role in inhibitory circuit dysfunction in autism. In Aim 1, we identify the molecular signaling pathways that mediate intrinsic plasticity in PV neurons induced by brief sensory deprivation. Prior work shows that deprivation rapidly increases Kv1 potassium currents, which elevates PV spike threshold. We will identify the molecular pathways for this plasticity, using a combination of immunohistochemistry and qHCR-FISH to detect alterations in protein and gene expression, and pharmacological and genetic tools to test causal involvement of candidate signaling pathways. We focus on candidate pathways that are known to regulate Kv1.1 channels. We also use single-nucleus RNAseq for unbiased discovery of regulated genes. Preliminary results implicate the Er81-KCNA1 pathway, which drives increased expression of Kv1.1. This work will yield molecular understanding and molecular markers of PV intrinsic plasticity, which we will use to characterize its prevalence and properties. Aim 2 tests the novel hypothesis that deficits in PV intrinsic plasticity are the underlying cause of PV circuit dysfunction in some genetic forms of autism, specifically for autism genes that regulate activity- dependent gene expression and/or Kv1.1 function in PV cells. We propose that due to loss of PV intrinsic plasticity, neural coding is destabilized in autism. We will test this hypothesis in Fmr1, Tsc2, and Cntnap2 transgenic mouse models of autism. As part of this work, we will test whether restoring gene expression selectively in PV cells rescues PV intrinsic plasticity and stabilizes pyramidal cell coding. If so, this would suggest a new therapeutic approach to autism in restoration of PV intrinsic excitability. Aim 3 tests for plasticity in SST circuits, which is little studied. In preliminary data, deprivation alters SST intrinsic excitability and other aspects of SST circuit function. This demonstrates that SST plasticity exists. We will characterize SST circuit plasticity and identify molecular mechanisms for SST intrinsic plasticity, to test for possible common mechanisms with PV intrinsic plasticity. Together, this grant will develop and test the novel hypothesis that plasticity of intrinsic excitability is a major form of plasticity in PV and SST interneurons that plays important roles in regulating cortical function and disease.
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