Original articleDecreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation
Introduction
The hippocampal formation (HF; including the dentate gyrus, subdivisions of Ammon’s Horn [CA1–CA4], subiculum, and parahippocampal gyrus) is a focus of schizophrenia research Torrey and Peterson 1974, Weinberger 1991, Weinberger 1999. Cholinergic afferents from the medial septum and diagonal band of Broca project to all layers of the hippocampus (Frotscher and Leranth 1985). Moreover, muscarinic cholinergic receptors are important to hippocampal function, including the processes of learning and memory Fadda et al 1996, Frotscher and Leranth 1985, McAlonan et al 1995. Alterations to the muscarinic cholinergic system of the HF may be primarily or secondarily involved in the pathophysiology of schizophrenia. Importantly, pre- and postsynaptic muscarinic receptors appear to modulate both cholinergic and noncholinergic activity in the hippocampus. Noncholinergic systems modulated by acetylcholine (ACh) include glutamate, γ-aminobutyric acid (GABA), noradrenalin, and serotonin, all of which have been implicated in schizophrenia Umbriaco et al 1995, Vizi and Kiss 1998. Conversely, there is evidence to suggest that noncholinergic systems including dopaminergic (Imperato et al 1994) and serotonergic Fujii et al 1997, Koyama et al 1999, Vizi and Kiss 1998 modulate hippocampal ACh release and associated muscarinic receptor activity. Interestingly, we have previously reported that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia Dean et al 1996, Naylor et al 1996. The altered serotonin transporter activity may be associated with increased levels of serotonin. As it has been shown that increased serotonergic activity in the hippocampus increases ACh efflux in the hippocampus Fujii et al 1997, Koyama et al 1999, we hypothesize that a down-regulation in the levels of hippocampal muscarinic receptors may occur in schizophrenia.
To test our hypothesis, we have measured the binding of [3H]pirenzepine ([3H]Pz) using quantitative autoradiography, in regions of the HF from subjects with and without schizophrenia. The muscarinic antagonist [3H]Pz was employed, as it binds selectively to M1 and M4 receptors Doods et al 1987, Hulme et al 19901 both of which are important for hippocampal neurochemistry Flynn et al 1995, Levey et al 1995, Vizi and Kiss 1998. Moreover, in light of the actions of the atypical antipsychotic drugs clozapine and olanzapine, which bind with high affinity to M1 and M4 receptors, we propose that of the five known types of muscarinic receptors, M1 and M4 receptors in particular may be important to the pathology and/or treatment of schizophrenia Bolden et al 1992, Bolden et al 1991, Bymaster et al 1999, Zorn et al 1994.
Section snippets
Tissue collection
After gaining ethical approval from the Human Ethics Committee of the Mental Health Research Institute of Victoria, human HF (dentate gyrus, CA1–CA4, subiculum, and parahippocampal gyrus) was collected at autopsy from the left-brain hemispheres of 15 subjects with a provisional diagnosis of schizophrenia. Tissue was also collected from the same brain region of the left-brain hemispheres of 18 subjects with no clinical history of psychiatric illness, or histopathological evidence of neurological
Results
The specific binding of [3H]Pz to sections of HF was >95% of TB (Figure 1). There was a significant decrease in the mean levels of [3H]Pz binding in all regions of the HF studied from schizophrenic compared to control subjects (Table 1, Table 2 and Figure 2). In addition, although there were regional differences in the mean levels of radioligand binding in the HF from control subjects (dentate gyrus < CA1 [p < .001] and CA2 [p < .05]; CA1 > CA3 [p < .001], CA4 [p < .001], subiculum [p <
Discussion
Based on the receptor selectivity of [3H]Pz binding Doods et al 1987, Hulme et al 1990, and the high and intermediate abundance of M1 and M4 receptors respectively in the HF (Levey et al 1995), our study suggests that the density of M1 and/or M4 receptors are decreased throughout the HF of subjects who had schizophrenia. Similarly, Perry and Perry (1980) previously measured a decrease in the density of [3H]QNB-labeled muscarinic receptors in the whole hippocampus from subjects who had
Acknowledgements
JMC was a recipient of a National Health and Medical Research Council Dora Lush Scholarship. BD is a NARSAD Young Investigator. The research was supported in part by The Rebecca L. Cooper Research Foundation.
The authors acknowledge the contribution made to this study by Mr. Geoffrey Pavey, Dr. Kenneth Opeskin, and the Victorian Institute of Forensic Medicine.
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