GABAergic mechanisms of hippocampal hyperactivity in schizophrenia

Abstract

Schizophrenia is associated with abnormalities of hippocampal structure and function. Neuroimaging studies have shown that the hippocampus is hyperactive in schizophrenia. Here we explore GABAergic mechanisms of this hippocampal hyperactivity. The initial evidence for GABAergic abnormalities of the hippocampus in schizophrenia came from post-mortem studies of interneuron number, protein expression, and gene expression. These studies revealed marked decreases in gene and protein expression of somatostatin-positive and parvalbumin-positive interneurons, and indicated reduced interneuron numbers. Animal studies of decreased parvalbumin and NMDA-receptor function have shown that selective abnormalities of hippocampal interneurons mimic some of the cognitive deficits and clinical features of schizophrenia. The post-mortem and animal studies are consistent with the neuroimaging finding of increased hippocampal activity in schizophrenia, which can explain some of the psychotic symptoms and cognitive deficits. Taken together, these findings may guide the development of biomarkers and the development of new treatments for psychosis.

Keywords: GABA; Hippocampus; Neuroimaging; Schizophrenia.

Figure 1. Parvalbumin-positive and Somatostatin-positive neurons in the human hippocampus

The photomicrographs show the cell bodies, axon and dendrites of parvalbumin-positive (left column) and somatostatin-positive (middle column) neurons in subfield CA1 of the human hippocampus, next to a schematic depiction of the position of subcellular components of pyramidal cells (right column; modified from (Spruston, 2008)). Cell somata of both interneuron populations are dispersed throughout the pyramidal cell layer. Parvalbumin-positive neurons have large somata and a high density of neurites throughout the pyramidal cell layer. A lesser density of neurites is seen in the stratum radiatum, with increasing density toward the stratum lacunosum. In contrast, somatostatin-positive neurons have smaller somata. In CA1, a group of these neurons is aligned at the border to the stratum oriens. Faint somatostatin-positive projections are seen in the pyramidal cell layer, but the highest density of neurites is seen in stratum moleculare. All scale bars = 100 μm.

Figure 2. Altered excitation/Inhibition balance in the human hippocampus

Panel A. The majority of neurons in the human hippocampus are large, excitatory (glutamatergic) pyramidal cells. Pyramidal cells are surrounded by local interneurons that can inhibit their firing pattern at various subcellular sites. Somatostatin-positive interneurons inhibit the distal dendrites in the stratum moleculare (apical tuft; orange column on the left). In contrast, parvalbumin-positive interneurons modulate pyramidal cells at more proximal dendrites and the cell body (panel A, green column on the right). Panel B. Somatostatin-positive interneurons control information flow arriving from the entorhinal cortex. Proximal apical dendrites in CA1 receive input primarily from CA3. Thus, parvalbumin neurons control pyramidal cell activity originating from both extrahippocampal and intrahippocampal sources. Panel C. A loss of somatostatin neuron activity will lead to a disinhibition of the input from the entorhinal cortex. Panel D. A loss of parvalbumin neurons will lead to asynchronous firing of pyramidal cells and increased excitatory drive from the hippocampus.