Physiological and molecular mechanisms of impaired PV circuit homeostasis in Autism mouse models

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PROJECT SUMMARY Parvalbumin (PV) neuron hypofunction and increased excitation-inhibition (E-I) ratio in feedforward cortical circuits likely contribute to abnormal sensory processing in Autism Spectrum Disorders, but the origins and molecular mechanisms of PV hypofunction, and its generalizability beyond feedforward circuits, remain unclear. Here, I will test the hypothesis that PV circuit hypofunction arises because of impaired homeostatic plasticity of PV circuits, that normally acts to maintain cortical excitability during periods of shifting sensory input. In L2/3 of whisker primary somatosensory cortex (S1), PV circuit homeostasis is robustly engaged by brief whisker deprivation, which reduces intrinsic excitability of PV neurons, decreasing feedforward inhibition. In Aim 1.1, I will use in vitro electrophysiological measurements of PV cell excitability to test for impaired PV circuit homeostasis in two ASD mouse models (Fmr1-/y and Tsc2+/-). These models share PV hypofunction but differ in several molecular and synaptic phenotypes, making them a powerful test case for whether the PV hypofunction may arise from a common source. Previous physiological studies have primarily focused on dysfunction in bottom-up feedforward circuits in ASDs, but recent reports in people with ASDs suggest that sensory processing issues may result from a functional deficiency in top-down feedback pathways, resulting in overreliance on feedforward input. Top-down pathways provide strong input to S1, but it is unknown whether the physiology of feedback pathways is altered in ASD mouse models and whether their alteration may also result from a failure of homeostasis in PV cells. In Aims 1.2 & 1.3, I will assess changes in baseline function and homeostatic plasticity of S2->S1 inputs to L2/3 pyramidal and PV cells in S1 using optogenetics. Understanding the molecular mechanisms that underlie impaired PV circuit homeostasis in ASDs may enable therapeutic interventions to restore PV circuit function. These molecular mechanisms are currently unknown. I will identify the molecular mechanisms underlying deprivation-induced weakening of PV intrinsic excitability, the key initial step in PV homeostasis. This is known to involve an increase in voltage-gated potassium (Kv) channel currents. The molecular mechanisms likely involve activity-dependent protein synthesis, which is reportedly dysregulated in both the Fmr1-/y and Tsc2+/- mice, though potentially in opposite directions. A promising candidate signaling pathway that could mediate PV circuit homeostasis is activity- dependent synthesis of transcription factor ER81 leading to increased Kv1.1 expression in PV cells. In Aim 2, I will use novel cell-specific genetic strategies to test the hypothesis that PV circuit homeostasis requires protein synthesis in vivo and involves activity-dependent synthesis of ER81 and increased Kv1.1- and this is impaired in ASD mice. I will also develop CRISPR tools to modulate Kv1.1 levels to rescue PV homeostasis in ASD mice, potentially leading to therapeutic approaches for ASDs.