Progress in Neuro-Psychopharmacology and Biological Psychiatry
Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia
Introduction
The posterior cingulate cortex (PCC), part of the corticolimbic system, is a brain area involved in memory, spatial orientation, and monitoring of eye movements (Vogt et al., 1992). Functional MRI data have shown that the PCC is a site of pathology in schizophrenia, as demonstrated by: 1) impaired posterior cingulate cortex functionality in a semantic task which relates to verbal memory deficits that are frequently observed in schizophrenia patients (Tendolkar et al., 2004); 2) an inability of schizophrenia patients to produce an increase in blood flow to the posterior cingulate in response to a recognition memory test, compared to healthy volunteers (Crespo-Facorro et al., 2001); and 3) a reduction in metabolic rate and volume in this region in schizophrenia patients compared to the controls (Haznedar et al., 2004, Mitelman et al., 2004). Furthermore, animal studies have shown that NMDA antagonists can selectively damage the PCC (Olney and Farber, 1995), and that this damage can be attenuated by gamma-aminobutyric acid A (GABAA) receptor agonists as well as anticholinergic drugs such as scopolamine and benztropine (Olney et al., 1991). This suggests that the muscarinic and GABAergic systems may play a role in NMDA antagonist-induced neurotoxicity in the PCC.
Muscarinic receptors are associated with cognition, attention, memory and motor control (Hyde and Crook, 2001), functions that are altered in schizophrenia. There are 5 muscarinic cholinergic receptors and all are G-protein coupled. Muscarinic receptors of the M1 subtype are primarily localised postsynaptically and are the most abundant of the muscarinic receptors in the cortex (Volpicelli and Levey, 2004). In contrast, M2 receptors are predominantly located presynaptically at the axonal terminals of the cholinergic neurons, where they inhibit acetylcholine release (Mash et al., 1985). M4 receptors have been shown to be postsynaptic in the cortex (Billard et al., 1995). Recently our group and others have found reduced M1 and M2 receptor binding in a region-specific manner in schizophrenia (Crook et al., 1999, Crook et al., 2000, Crook et al., 2001, Dean et al., 1996, Dean et al., 2004, Deng and Huang, 2005, Katerina et al., 2004, Zavitsanou et al., 2005).
GABA is the major inhibitory neurotransmitter in the brain. There are two receptors that mediate GABA neurotransmission in the brain; GABAA and GABAB. GABAA receptors are ligand gated chloride ion channels (Steiger and Russek, 2004). GABA was originally implicated in schizophrenia when low cerebrospinal fluid GABA levels were found in schizophrenia patients (van Kammen et al., 1980). Since then, studies have continued to provide strong evidence of GABAergic hypofunction in the schizophrenia brain. Decreased mRNA expression of the 67 kDa isoform of glutamate decarboxylase (GAD67), the enzyme responsible for synthesizing GABA, has been reported in the dorsolateral prefrontal cortex in schizophrenia (Akbarian et al., 1995), and reductions in GABA in nucleus accumbens and thalamus have also been found in schizophrenia (Perry et al., 1979). Furthermore, reductions in GABA uptake sites have been reported in prefrontal cortex, amygdala, and hippocampus in schizophrenia (Reynolds et al., 1990, Simpson et al., 1989).
In view of the above evidence, the present study examined the hypothesis that muscarinic and GABA receptors are altered in the posterior cingulate cortex in schizophrenia. Using quantitative autoradiography, we compared the binding of [3H]pirenzepine, [3H]AF-DX 384, and [3H]muscimol to M1/4, M2/4 and GABAA receptors in the posterior cingulate cortex of schizophrenia subjects and matched controls.
Section snippets
Post-mortem brain tissue
Human brain tissue from the PCC (left hemisphere) was obtained from the New South Wales Tissue Resource Centre at the University of Sydney. Ethical approval for this study was granted by the University of Wollongong Human Research Ethics Committee (Approval No. HE99/22). Ten male subjects without a known history of psychiatric illness and ten male subjects with a diagnosis of schizophrenia, matched for age and post-mortem interval (PMI), were used in this study (Table 1). Subjects were excluded
Laminar distribution of [3H]pirenzepine, [3H]AF-DX 384, and [3H]muscimol binding in the PCC
Specific binding of [3H]pirenzepine, [3H]AF-DX 384 and [3H]muscimol was observed in all cortical layers of the PCC and was > 95% of total binding for all the three ligands. [3H]pirenzepine appeared to display the highest density of binding sites followed by [3H]AF-DX 384. [3H]muscimol displayed the lowest density of binding sites.
Binding sites labelled by these ligands appeared to have differential distribution patterns among the layers of the PCC. The principal laminar patterns of each ligand
Discussion
The present study investigated the binding of the acetylcholine muscarinic receptor antagonists [3H]pirenzepine and [3H]AF-DX 384, and the GABAA receptor antagonist [3H]muscimol in the PCC of subjects with schizophrenia. These radioligands bind to M1/M4, M2/M4, and GABAA receptors respectively. A significant down-regulation of M1/M4 muscarinic receptors and an upregulation of GABAA receptors was observed in the PCC in schizophrenia. No changes in M2/M4 receptor density were observed between the
Conclusion
In conclusion, the decrease in M1 receptor density and the increase in GABAA receptor density in schizophrenia suggest an involvement of these two systems in the pathology of the PCC in schizophrenia. It is suggested that these changes are the result of increased cortical acetylcholine and decreased cortical GABA. The observed changes may be due to NMDA receptor hypofunction in this region. However, further research is needed to determine the mechanism of these changes, and the examination of a
Acknowledgements
This work was supported by the St. George Foundation, and the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD) utilising the infrastructure funding from NSW Health. Post-mortem brain tissues were received from the NSW Tissue Resource Centre, which is supported by the University of Sydney, NISAD, National Institute of Alcohol Abuse and Alcoholism and NSW Department of Health. The Beta Imager was provided with funds raised by the Wollongong Lord Mayor's Schizophrenia Awareness
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