Altered Cortical Ensembles in Mouse Models of Schizophrenia

Abstract

Summary In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine administration (KET) and Df(16)A+/−, modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gamma-band abnormalities similar to patient studies. Two-photon calcium imaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles) which was not a simple consequence of altered single neuron activity. This effect was present in ongoing and sensory evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an “attractor” disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia.

Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits

“…Dysregulation of GABAergic inhibition in the brain is a candidate mechanism underlying schizophrenia and other neurodevelopmental disorders (Uhlhaas and Singer, 2010; Hamm and Yuste, 2016; Hamm et al, 2017). Schizophrenic patients exhibit altered gamma oscillations (Karouni et al, 2010; Lee et al, 2010; Uhlhaas and Singer, 2010), and deficits in basic sensory processing and perception (Slaghuis, 2004; Martinez et al, 2008; Tan et al, 2013; Serrano-Pedraza et al, 2014).…”

Effects of chronic ketamine on hippocampal cross‐frequency coupling: implications for schizophrenia pathophysiology

“…Yet findings from chronic models are more mixed; while Kittelberger et al (2012) find chronic decreases in CA1 theta and gamma power, some (McNally et al, 2013;Sullivan et al, 2015;Phoumthipphavong et al, 2016) report increase in gamma amplitude in cortical networks, changes in the peak frequency of gamma oscillations or no change in power. In cortical networks, chronic NMDAR antagonism does not appear to be a consequence of single-neuron activity but rather the interaction of large neuron ensembles during sensory-evoked activity (Hamm et al, 2017). More subtle changes in CFC could provide a potential explanation for why some clinical studies (Symond et al, 2005;Cho et al, 2006) report reduced gamma power in patients with schizophrenia, while others (Tekell et al, 2005;Flynn et al, 2008) report increased power and some (Spencer et al, 2008) 2014) that novel sensory experiences can alter the relation of locomotive speed to theta and gamma characteristics.…”

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

“…The existence of mouse models of individual or multiple genes within the region of synteny to the human 22q11.2 region also lays the foundation for a broad array of translational research to understand molecular mechanisms. 17,18,28–32 …”