Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner

J. J. Donegan, A. M. Boley, J. Yamaguchi, Glenn M Toney, Daniel J Lodge

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2819
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

hippocampus
Neurons
Hippocampus
Dopamine
Modulation
modulation
Networks (circuits)
GABA-A Receptors
Nucleus Accumbens
schizophrenia
dopamine
Dopaminergic Neurons
neurons
nuclei
psychoses
Schizophrenia
projection
rodents
cortexes
Prefrontal Cortex

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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title = "Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner",
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.",
author = "Donegan, {J. J.} and Boley, {A. M.} and J. Yamaguchi and Toney, {Glenn M} and Lodge, {Daniel J}",
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AU - Yamaguchi, J.

AU - Toney, Glenn M

AU - Lodge, Daniel J

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AB - 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.

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