Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder

Area of Science:

• Neuroscience
• Psychiatry
• Molecular Biology

Background:

• Postmortem studies suggest uncoupling of GABA and benzodiazepine binding sites on hippocampal GABA(A) receptors in schizophrenia.
• GABA(A) receptor function is determined by its subunit composition, influencing ligand binding characteristics.

Purpose of the Study:

• To investigate changes in GABA(A) receptor subunit composition in the hippocampus of individuals with schizophrenia and bipolar I disorder.
• To test the hypothesis that altered receptor subunit composition underlies the uncoupling of GABA and benzodiazepine binding sites.

Main Methods:

• Postmortem hippocampal tissue from schizophrenic, bipolar I disorder, and control subjects was used.
• Quantification of GABA ([(3)H]muscimol) and benzodiazepine ([(3)H]flumazenil) binding sites.
• Assessment of zolpidem- and clonazepam-displaceable [(3)H]flumazenil binding to determine subunit-specific changes.

Main Results:

• Schizophrenia: Decreased [(3)H]muscimol and [(3)H]flumazenil binding in the CA2 region, with reduced zolpidem-sensitive and -insensitive binding.
• Bipolar I Disorder: Regionally specific changes in [(3)H]muscimol binding; decreased zolpidem-sensitive and increased zolpidem-insensitive [(3)H]flumazenil binding.
• The increase in zolpidem-insensitive binding suggests a rise in GABA(A) receptors containing the alpha5 subunit in bipolar I disorder.

Conclusions:

• Altered GABA(A) receptor subunit composition is implicated in the pathophysiology of schizophrenia and bipolar I disorder.
• Specific changes in hippocampal GABA(A) receptor subtypes may contribute to the distinct clinical features of these disorders.
• Findings highlight the role of GABAergic system dysregulation in severe mental illnesses.