Genetic and Synaptic Mechanisms of State Representation Impairments in Mice

PROJECT SUMMARY: PROJECT 2 The purpose of PROJECT 2 is to use mice as an experimental system to investigate cellular and synaptic neurophysiology that captures core features of medial prefrontal cortex (mPFC) microcircuit dysfunction that may be related to information processing failures in psychosis. The organizing premise of our Center is that psychosis involves dysfunctional state representation processes, which we will study across species at the behavioral level using the Dot Pattern Expectancy (DPX) task and the Bandit probabilistic reversal learning task. Guided by published neurophysiology findings in the prefrontal cortex of nonhuman primates after systemic NMDA receptor blockade, we propose to measure the coordinated activity of neuronal ensembles in the medial prefrontal cortex of mice performing these two tasks. In Aim 1, we will use genetic manipulations to selectively delete NMDA receptors from the medial prefrontal cortex, while also testing the same pharmacological manipulation of NMDA receptors used in PROJECT 1. In Aim 2, we will study mouse lines carrying the three most common genetic variants associated with psychosis with genome-wide significance. Behavior and neurophysiology data will be passed to the COMPUTATIONAL CORE, to conduct the same causal discovery analyses and computational modeling used across all PROJECTS. In Aim 3, we will probe synaptic function in the medial prefrontal cortex of each mutant mouse line, to determine whether differences in the synaptic microcircuit (i.e., local connections between excitatory and inhibitory neurons) are related to behavioral and disease phenotypes. Data from the synaptic level will be used to evaluate and inform the Neurophysiology- Level attractor network model, which includes synaptic weights as key parameters. Our central hypothesis is that mutant mice will exhibit synaptic dysfunction and related changes in mPFC neurophysiology, which we expect to have a negative impact on various state representation processes. We expect to observe heterogeneous impairments across different genetic manipulations, mirroring the heterogeneity present in patient populations (PROJECTS 3 & 4), and providing fodder for computational modeling and causal discovery analyses. Within our Center, these experiments provide a unique opportunity for precise measurement and manipulation of both disease-related dysfunction and treatment-related plasticity in the medial prefrontal cortex microcircuit, while translating results across species through computational analyses.