Abstract
Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Here we attempt to reverse this deficit by overexpression of the α5-GABAA receptor within the ventral hippocampus (vHipp). Indeed, this is sufficient to normalize vHipp activity and downstream alterations in dopamine neuron function in the MAM rodent model. This approach also attenuated behavioral deficits in cognitive flexibility. To understand the specific pathways that mediate these effects, we used chemogenetics to manipulate discrete projections from the vHipp to the nucleus accumbens (NAc) or prefrontal cortex (mPFC). We found that inhibition of the vHipp-NAc, but not the vHipp-mPFC pathway, normalized aberrant dopamine neuron activity. Conversely, inhibition of the vHipp-mPFC improved cognitive function. Taken together, these results demonstrate that restoring GABAergic signaling in the vHipp improves schizophrenia-like deficits and that distinct behavioral alterations are mediated by discrete projections from the vHipp to the NAc and mPFC.
Highlights
Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling
We found that α5 overexpression increased tonic GABA currents and normalized aberrant pyramidal cell activity in the ventral hippocampus (vHipp)
We found that overexpressing the α5 subunit in pyramidal cells of the vHipp increased tonic GABA currents without affecting phasic activity
Summary
Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Systemic α5 agonists normalize dopamine signaling and improve behavioral correlates of positive symptoms in rodent models of schizophrenia[20], suggesting that this subunit of the GABAA receptor may be a viable therapeutic target. It is unclear whether enhancing signaling at the α5 GABAA subunit would improve cognitive symptoms, which are poorly treated by currently prescribed antidepressants. We found that α5 overexpression increased tonic GABA currents and normalized aberrant pyramidal cell activity in the vHipp This approach normalized aberrant dopamine signaling and cognitive function in a rodent model of schizophrenia, suggesting this may be a promising novel treatment strategy for schizophrenia. These experiments identify a novel approach for treating schizophrenia and provide insight into the anatomical and neurochemical pathways associated with discrete dimensions of schizophrenia, so that therapeutics can be developed with improved efficacy for treating multiple symptom domains
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