Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning

Abstract

Variation in the gene DTNBP1 encoding the protein dysbindin-1 is often associated with elevated risk for schizophrenia and with cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1 or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor co-agonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia.

Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice—Potential Link to Cognitive Impairment in Schizophrenia

“…Since NMDA receptor function is closely related to ARC, and NMDA activity is down regulated in the dys1−/− mouse model of schizophrenia [38-40,6], we determined whether SREBP1 expression could be altered in NMDA receptor1 (NR1) hypomorph mice. Significant reduction in nSREBP1 was found in the brains of these mice (Figure 3D).…”

The NMDA Receptor and Schizophrenia

“…Other genetic models have found that deleting the GluN1 subunit of the NMDAR, either constitutively, in corticolimbic inhibitory neurons, in parvalbumin inhibitory neurons, or in forebrain pyramidal neurons leads to cognitive, social, and electrophysiological (i.e., gamma band oscillations) changes reminiscent of schizophrenia (Belforte et al, 2009; Jadi, Margarita Behrens, & Sejnowski, 2015; Tatard-Leitman et al, 2015). Mice lacking the protein dybsindin, (an original candidate risk gene), which is reduced in schizophrenia, display NMDAR hypofunction, disrupted inhibitory transmission, hyperexcitability in the PFC, as well as deficits in working memory and learning (Carlson et al, 2011; Glen et al, 2014; Karlsgodt et al, 2011; Yuan et al, 2015). …”

Electrophysiological Endophenotypes in Rodent Models of Schizophrenia and Psychosis

“…Knockout mice lacking the dysbindin have reduced auditory evoked potentials and disturbed gamma-frequency oscillations; inhibition onto cortical neurons is also reduced in these mice, as is parvalbumin immunoreactivity (58). Decreases in excitatory evoked and miniature post-synaptic potentials suggest similar reductions in excitation in these mutants; short-term plasticity is also reduced (56), as is a form of long-term potentiation in the hippocampus (59). …”

“…Several SCZ susceptibility genes were implicated in impaired synaptic plasticity including Dgcr8 (31, 51) , NRG-1 (64) and Dysbindin (56, 59) . Disrupted synaptic plasticity mechanisms could cause a range of downstream, secondary neurophysiological effects.…”