Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors

Abstract

Recent findings from in vivo-imaging and human post-mortem tissue studies in schizophrenic psychosis (SzP), have demonstrated functional and molecular changes in hippocampal subfields that can be associated with hippocampal hyperexcitability. In this study, we used a subfield-specific GluN1 knockout mouse with a disease-like molecular perturbation expressed only in hippocampal dentate gyrus (DG) and assessed its association with hippocampal physiology and psychosis-like behaviors. First, we used whole-cell patch-clamp recordings to measure the physiological changes in hippocampal subfields and cFos immunohistochemistry to examine cellular excitability. DG-GluN1 KO mice show CA3 cellular hyperactivity, detected using two approaches: (1) increased excitatory glutamate transmission at mossy fibers (MF)-CA3 synapses, and (2) an increased number of cFos-activated pyramidal neurons in CA3, an outcome that appears to project downstream to CA1 and basolateral amygdala (BLA). Furthermore, we examined psychosis-like behaviors and pathological memory processing; these show an increase in fear conditioning (FC), a reduction in prepulse inhibition (PPI) in the KO animal, along with a deterioration in memory accuracy with Morris Water Maze (MWM) and reduced social memory (SM). Moreover, with DREADD vectors, we demonstrate a remarkably similar behavioral profile when we induce CA3 hyperactivity. These hippocampal subfield changes could provide the basis for the observed increase in human hippocampal activity in SzP, based on the shared DG-specific GluN1 reduction. With further characterization, these animal model systems may serve as targets to test psychosis mechanisms related to hippocampus and assess potential hippocampus-directed treatments.

Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function

“…Mossy fiber density has previously been negatively correlated with exploratory activity in the open field ( Crusio et al., 1989 ) and active avoidance learning ( Schwegler et al., 1981 ), however, those studies focused primarily on the size of the infra-/intrapyramidal band. A relation between the length of the infrapyramidal band and reversal learning in the Morris water maze has also been shown previously ( McNamara et al., 1998 ), while increased MF transmission in DG-specific GluN1 null mutants as well as hyperactivation of the ventral CA3 but not dorsal CA3 with DREADD receptors are accompanied by a disturbance of social memory ( Segev et al., 2018 ). Our current data suggest that deficits in the suprapyramidal band of TG mice are indeed associated with altered exploratory activity and reduced performance in avoidance, social and spatial reversal learning.…”

Multiple omic investigations of freeze tolerance adaptation in the aquatic ectothermic vertebrate, the Amur sleeper

“…Fbxo2 is a subunit of the ubiquitin protein ligase complex SCF, which function in Ub-mediated degradation of GluN1 subunit of the NMDA receptors that mainly mediate neural excitatory transmission (Otsu, et al 2019). GluN1 knockout mice have hyperactivity compared to wild-type mice (Segev, et al 2020). Given that fbxo2 has been shown to facilitate the degradation of the GluN1 (Atkin, et al 2015), the genetic changes of fbxo2 in Amur sleeper may suggest an inhibition of excitatory transmission.…”

Using internal memory representations in associative learning to study hallucination-like phenomenon

“…Recent work additionally shows that the interaction between the hippocampus and the orbitofrontal cortex is important for inferring future outcomes using internal representations under sensory preconditioning, a learning paradigm that shares some procedural similarity with representation-mediated learning (Wang et al, 2020). In addition to its role in dopaminergic regulation, consideration of the hippocampus as a component of a network contributing to neurocognitive dysfunction in schizophrenia may afford the opportunity to gain efficacy for cognitive deficits that are not remediated by antipsychotics that target dopaminergic function (Koh et al, 2018a;Scott and Tamminga, 2018;Segev et al, 2018;Smucny et al, 2015). Further extensions in forebrain cortical circuitry are under study within the affected network in psychiatric illness (e.g., Donegan et al, 2019;Nelson et al, 2020).…”