Abstract
Reductions of glutamate acid decarboxylase (GAD67) and subsequent GABA levels have been consistently observed in neuropsychiatric disorders like schizophrenia and depression, but it has remained unclear how GABAergic dysfunction contributes to different symptoms of the diseases. To address this issue, we investigated male mice haplodeficient for GAD67 (GAD67+/GFP mice), which showed a reduced social interaction, social dominance and increased immobility in the forced swim test. No differences were found in rotarod performance and sensorimotor gating. We also addressed potential effects of social deprivation, which is known, during early life, to affect GABAergic function and induces behavioral abnormalities similar to the symptoms found in psychiatric disorders. Indeed, social isolation of GAD67+/GFP mice provoked increased rearing activity in the social interaction test and hyperlocomotion on elevated plus maze. Since GABA closely interacts with the dopaminergic, serotonergic and cholinergic neurotransmitter systems, we investigated GAD67+/GFP and GAD67+/+ mice for morphological markers of the latter systems and found increased tyrosine hydroxylase (TH)-IR fiber densities in CA1 of dorsal hippocampus. By contrast, no differences in numbers and densities of TH-positive neurons of the midbrain dopamine regions, serotonin (5-HT) neurons of the raphe nuclei, or choline acetyltransferase (ChAT)-expressing neurons of basal forebrain and their respective terminal fields were observed. Our results indicate that GAD67 haplodeficiency impairs sociability and increases vulnerability to social stress, provokes depressive-like behavior and alters the catecholaminergic innervation in brain areas associated with schizophrenia. GAD67+/GFP mice may provide a useful model for studying the impact of GABAergic dysfunction as related to neuropsychiatric disorders.
Highlights
A corticolimbic GABAergic dysfunction has been implicated in the pathophysiology of neuropsychiatric disorders like schizophrenia and major depressive disorder (MDD) (Benes and Berretta 2001; Fatemi et al 2005)
Post hoc analyses for isolated GAD67+/green fluorescence protein (GFP) mice, compared with isolated GAD67+/+ mice, showed a trend towards a lower time spent in social contact (t = − 2.02, df = 15, p = 0.062, Fig. 1a) and significantly less time spent in passive social interaction (t = − 2.32, df = 15, p < 0.05, Fig. 1b), indicating that post-weaning social isolation affects social behavior in GAD67+/GFP mice
We found that GAD67+/GFP mice lost significantly more bouts, independent from housing condition (Fig. 1e, binary logistic model followed by Wald Chi-square test, GENOTYPE effect: Wald-χ2(1) = 7.18, Exp(B) = 0.39 (95% confidence interval (CI) = 0.20–0.78), p = 0.007; HOUSING effect: Wald-χ2(1) = 0.12, Exp(B) = 0.89, p > 0.05; HOUSING and GENOTYPE interaction: Wald-χ2 (1) = 0.24, Exp(B) = 1.27, p > 0.05, demonstrating that GAD67+/GFP mice are less dominant than wild-type mice when paired against each other
Summary
A corticolimbic GABAergic dysfunction has been implicated in the pathophysiology of neuropsychiatric disorders like schizophrenia and major depressive disorder (MDD) (Benes and Berretta 2001; Fatemi et al 2005). The most consistent findings in post-mortem brain studies of schizophrenia patients are reduced numbers of parvalbumin (PARV)-containing GABAergic interneurons and a decreased expression of the 67-kDa isoform of the GABA-synthesizing enzyme glutamate acid decarboxylase (GAD67) in cerebral cortex and hippocampus (Akbarian et al 1995; Guidotti et al 2000; Hashimoto et al 2003; Lewis et al 2005). In contrast to GAD67, only inconsistent findings in schizophrenia are reported for the 65-kDa (GAD65) isoform (Guidotti et al 2000; Glausier et al 2015; de Jonge et al 2017). Schizophrenia is further characterized by heterogeneous clinical symptoms including social withdrawal, avolition, hyperactivity, depressive symptoms, deficits in sensorimotor gating and increased risk for aggression (Andreasen et al 1990; Braff et al 2001)
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