GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study

Abstract

Background: Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and residual schizophrenia. Methods: GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem schizophrenia patient samples (10 paranoid and 6 residual schizophrenia cases) were compared with those from 16 matched controls. Results: Overall, schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P = 0.033). However, the diagnostic subgroups differed significantly (P < 0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus residual patients (P = 0.036) and controls (P < 0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus residual schizophrenia cases (P = 0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r = 0.850, P = 0.004; left: r = 0.800, P = 0.010). Conclusion: Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system.