Hippocampal neurons in schizophrenia

Abstract

The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal interneurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia.

Fig. 1

High-resolution MRI of human hippocampus. A Histogram of hippocampal volume along the anterior-posterior axis. B–D Three orthogonal views of the human hippocampus in a normal subject. The amygdala (yellow) can be separated from the uncus (red), hippocampal body (dark blue) and hippocampal tail (light blue). The slices represent a horizontal (B), coronal (C), and sagittal (D) view

Fig. 2

Three levels of hippocampal anatomy. A High resolution coronal MRI of the human hippocampus at the level of the hippocampal body. B Schematic diagram of the regions of the human hippocampal formation and their major connections. The entorhinal cortex (EC) sends direct projections and indirect projections via the dentate gyrus (DG) and cornu Ammonis sector CA2/3 to CA1, from which output is relayed via the subiculum (S) back to EC. C The laminar organization of the human hippocampus shown for cornu Ammonis sector CA2/3. Input arrives at dendrites of pyramidal cells in the stratum radiatum/lacunosum/moleculare (RLM), output leaves via fibers in the stratum oriens (O). The two neuronal types in the pyramidal cell layer are the pyramidal shaped principal cells and the nonpyramidal shaped interneuron. At least three types of inhibitory projections can arise from hippocampal interneurons: recurrent inhibition (driven by a collateral of a glutamatergic axon), direct inhibition of a pyramidal cell, and disinhibition of a pyramidal cell (via interneuron-interneuron projection)