Chronic Axon Hypofunction in Maternal Immune Activation Models of Neurodevelopmental Disorders

点击翻译按钮获取中文摘要

New Summary: Maternal infection during pregnancy is an established risk factor for neurodevelopmental disorders, including Autism Spectrum Disorders (ASD), yet little is known about how immune insults alter neural circuitry in the developing brain and, as a result, impair behavior. One potential site for immune effects is the medial prefrontal cortex (mPFC), which plays a critical role in the higher-order social and cognitive functions compromised in disorders of altered neural development. Through the support of an exploratory R21 grant, we used a mouse model of Maternal Immune Activation (MIA) and developed a silicon probe-based multichannel recording system for high-throughput functional analysis of mPFC circuitry. Using this approach, we examined mPFC in adult offspring following maternal exposure to a viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), and identified an unexpected hypofunction in the output fibers of layer 5 projection neurons as the central defect in the mPFC. In particular, layer 5 axons were less able to sustain output during prolonged activity, and their temporal precision was impaired. Transcriptomic profiling of the mPFC revealed a downregulation of the cell adhesion molecule L1cam, a putative regulator of axonal excitability. Here the proposed work will use the same mouse MIA model to determine the functional ramifications of axonal hypoactivity on specific long-range targets of the mPFC that mediate behaviors dysregulated in ASD and related disorders – mediodorsal thalamus (MD), basolateral amygdala (BLA), and nucleus accumbens (NAc). Aim 1 of this proposal will test whether direct recruitment and/or indirect feedforward inhibition of principal cells in these subcortical regions is impaired in offspring exposed to maternal immune activation (MIA). Layer 5 mPFC projections will be specifically targeted for optogenetic stimulation with viral approaches. In Aim 2, we will augment layer 5 output with complementary genetic (L1cam rescue) or optogenetic (SSFO-driven enhanced excitability) approaches to determine whether this restores L5 output and rescues ASD-related deficits. In Aim 3, we will test for generality of our findings in MIA models and cortical regions. First, we will test whether MIA induced by lipo-polysaccharide (LPS) has similar effects as poly(I:C) on mPFC axonal function. Next we will determine whether somatosensory cortex, another cortical region implicated in ASD behaviors, also shows specific MIA induced changes in layer 5 axonal function, as might be expected if midgestational MIA broadly affects layer 5 cortical neurons at a critical step in their development. The results of the proposed experiments could both help to explain pathogenesis of ASD and other neurodevelopmental disorders and identify a molecular pathway that could be targeted to restore behavior.