Disrupted‐in‐schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization

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.

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity

“…The Ndel1 enzyme activity was measured in the serum and the selected brain regions collected one hour after administration of these psychostimulants or vehicle (n=8, two-way analysis of variance (ANOVA), Tukey post-hoc comparison test *p⩽0.05). Kaefer et al, 2019), with diminished high-affinity dopamine D2 receptor activity (similar to that observed in psychosis) (Seeman, 2011), and with aberrant dopamine neuroanatomy (Sasaki et al, 2005). Quantitative proteomics of synaptosomal fractions of tgDISC1 animals showed profound synaptic dysregulation in the dorsal striatum (Sialana et al, 2018), which is also in good agreement with the contrasting reduced connectivity between ventral striatum and substantia nigra reported in TRS (White et al, 2016), and as it was also demonstrated here for the defective striatal neuronal distribution in tgDISC1 compared to littermate WT control.…”

“…Mechanistically, we hypothesize that DISC1 aberrant intermolecular interactions or aggregation, as reported in tg DISC1 (Trossbach et al, 2016), may cause loss of functions, such as those mediated by DISC1 interaction with Ndel1 (Kamiya et al, 2006; Leliveld et al, 2008), since Ndel1 activity is modulated by DISC1 binding (Hayashi et al, 2005, 2010). DISC1 overexpression and misassembly were both associated with AMPH supersensitivity (Trossbach et al, 2016), with deficits in long-term memory and attention-related behavior (Hamburg et al, 2016; Kaefer et al, 2019), with diminished high-affinity dopamine D2 receptor activity (similar to that observed in psychosis) (Seeman, 2011), and with aberrant dopamine neuroanatomy (Sasaki et al, 2005). Quantitative proteomics of synaptosomal fractions of tg DISC1 animals showed profound synaptic dysregulation in the dorsal striatum (Sialana et al, 2018), which is also in good agreement with the contrasting reduced connectivity between ventral striatum and substantia nigra reported in TRS (White et al, 2016), and as it was also demonstrated here for the defective striatal neuronal distribution in tg DISC1 compared to littermate WT control.…”

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

“…Differences in theta phase preference between novel and familiar environments have been reported previously in WT rats (Lever et al, 2010, Fernandez-Ruiz et al, 2017, Kaefer et al, 2019). However, in those studies, novelty was associated with later firing relative to theta phase compared to a familiar environment, whereas we saw earlier theta phase firing on Day 1 than Day 2 in our novel environment in WT rats.…”

The structure of hippocampal CA1 interactions optimizes spatial coding across experience

“…We next analyzed CA1 tetrode recordings of six rats exploring familiar and novel 2D environments separated by a short period of rest (Fig. 1C) (37, 38). Putative units were filtered by using several clustering quality measures (39–41) to ensure that they were well isolated (Fig.…”