Disrupted-in-schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization.

Karola Kaefer,Jozsef Csicsvari,Carsten Korth,Hugo Malagon‐Vina,Svenja V Trossbach,Desiree D Dickerson,Joseph O'Neill

doi:10.1002/hipo.23076

Abstract

Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single‐unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted‐in‐Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention‐related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed‐modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location‐independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty‐induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.

Highlights

Chronic mental illnesses (CMI), such as schizophrenia and recurrent affective disorders, are highly heritable and have been associated with a large number of genetic loci (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014)
We found that pyramidal cells of tgDISC1 animals had a lower firing rate during Sharp wave ripple (SWR) occurring in the sleep/rest session after both the familiar and novel environment exploration (Wilcoxon Rank-Sum test; familiar: p = 2.74e − 11, novel: p = 1.13e − 12; Figure 5a)
Our results demonstrate that the aggregation of Disrupted-in-schizophrenia 1 (DISC1) protein, a model of sporadic CMI, leads to alterations in hippocampal CA1 activity patterns at both individual cell and population levels

Summary

| INTRODUCTION

Chronic mental illnesses (CMI), such as schizophrenia and recurrent affective disorders, are highly heritable and have been associated with a large number of genetic loci (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). A subgroup of postmortem brains of patients diagnosed with affective disorders or schizophrenia expressed significant fractions of DISC1 protein aggregates (Leliveld et al, 2008) Based on these findings, a rat model has been developed that transgenically overexpresses nonmutant, full-length DISC1 in the central nervous system (tgDISC1 rat), leading to aggregates of DISC1 protein, a dopamine system disturbance in brain areas including the hippocampus and dopamine- and attention-related behavioral deficits (Trossbach et al, 2016; Wang et al, 2017). TgDISC1 pyramidal cells displayed reduced firing during SWRs. We demonstrate that aggregation of a nonmutant protein and resulting downstream effects can lead to a wide range of impairments in hippocampal neural circuit function, which may underlie behavioral deficits

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION