Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Abstract

DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.GABAergic | γ-oscillation | hippocampus | evoked response spectral perturbation | Sandy mouse P atients with schizophrenia have reduced amplitude and gating of auditory event-related potentials (ERPs) (1, 2). Recent clinical studies also show abnormal γ-band oscillations (30-100 Hz) as an endophenotype of the illness that is associated with reduced cognitive function (3-7). Work in animal models shows a prominent role of cortical inhibitory networks in generating γ-oscillations (8, 9), which in turn, supports the role of aberrant GABAergic inhibition as an important potential component of schizophrenia (4,7,10,11). The GABA-producing enzyme glutamic acid decarboxylase is dysregulated in schizophrenia, and postsynaptic GABA A receptors are dysregulated as well (4). Risk alleles for GABA A receptor subunits are also associated with the disease (12, 13), although linkage is weaker than the linkage found with dysbindin-1 and other candidate genes such as DISC1 (14). At the anatomical level, there is a loss of immunoreactivity for parvalbumin (PV) in schizophrenia. PV is a calcium-binding protein marker for a class of fast-spiking GABAergic neurons. It is debated whether reduced PV in postmortem studies is caused by reduction in cell number or merely loss of protein expression. In either case, reduced PV immunoreactivity suggests disruption of an important source of local circuit inhibition (4, 15).Although clinical electrophysiological and postmortem anatomical findings support the role of GABA dysfunction in schizophrenia, a larger set of schizophrenia risk haplotypes are thought to confer reduced NMDA receptor-mediated function and changes in glutamatergic transmission [e.g., DISC1; Neuregu...

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

“…Cortical PV + interneuron pathology, particularly in the hippocampus, is a frequent feature of rodent models of schizophrenia pathogenesis and may be an outcome common to multiple susceptibility pathways in this disorder (6,7,12,28). The current study examines the impact of the loss of a major regulator of cortical PV + interneuron progenitor proliferation.…”

“…Although we expect these abnormalities to have effects on cognition and behavior, we and others have observed no evidence for qualitative sensory or motor (including cerebellar) phenotypes that would confound psychomotor or cognitive assessments used in this study. Notably, in schizophrenia, and in several rodent models of genetic susceptibility, hippocampal interneuron deficits occur in the context of cerebral cortical thinning, cerebellar pathology, and cell metabolic abnormalities (6,28,29,(33)(34)(35). dependent cognition assessed using the fear conditioning paradigm described for Fig.…”

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

“…From these studies, we have learned the key roles played by schizophrenia risk gene products such as TrkB, ErbB4, (receptors for brain-derived neurotrophic factor and neuregulin, respectively), dysbindin, and cannabinoid receptor 1 in the maturation process of PV + neurons (30,36,63,239,253). Interestingly, it was recently shown that deletion of selenoprotein expression or of the Se-dependent glutathione peroxidase 4 severely affects the maturation of PV + neurons (245).…”

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

“…[36][37][38] Ultimately, interneuron dysfunction could contribute to altered sensory perception, 39 deficits in working memory, 18,40 attention, 41 and learning. 42 Recent studies have revealed anomalies in hippocampal and/or prefrontal PVI in many preclinical animal models aiming to reproduce genetic vulnerabilities [43][44][45][46] or environmental risk factors 47 such as prenatal maternal stress, 48 maternal and perinatal immune challenge, 49,50 hypoxia, 51,52 early-life iron deficiency, 53 maternal separation, 54 and social isolation. 55,56 Similarly, nongenetic developmental models also result in altered prefrontal PVI.…”