4 October 2017: Unreliable neocortical ensemble activity in pharmacological and genetic mouse models supports an attractor pathophysiology of schizophrenia

Jordan Hamm
Department of Biological Sciences
Columbia University

While prefrontal cortex and brain-wide, interregional networks are often studied in major neurological and psychiatric disorders, synaptic and cell-type specific pathophysiology has been identified in nearly all cortical areas in diseases like schizophrenia (SZ), suggesting that neuronal circuit function at the most basic level could play a critical role. Two-photon calcium imaging (2P-Ca++) studies in rodents have shown that local neuron populations in neocortical circuits (<1mm3) display distinct activity patterns made up of coactive “ensembles”, a level of detailed dynamics not captured by gross level (EEG, fMRI) or single neuron recordings. These activity patterns repeat during basic sensory and cognitive processing and also spontaneously at rest, suggesting that they make up the preferred, semi-stable “attractor” states of the cortex. Here I present findings from distinct mouse models of SZ-relevant disease processes (NMDA-receptor block, 22q11.2 microdeletion) that support the notion that a disorganization of local ensembles and the underlying “attractor” landscape could underlie basic perceptual and cognitive deficits in the disease. Interestingly, while acute manipulations of excitation, inhibition, or top-down inputs recreated cortical processing abnormalities at the single neuron level, key deficits in population-level synchrony patterns were only observed after chronic disease-relevant manipulations or in genetic models. Implications and future approaches for understanding and targeting altered synaptic plasticity processes across key neurodevelopmental periods will be discussed.