Schizophrenia has been associated with at least two receptor complexes, namely, dopamine and GLU. Theories have been developed which invoke hypotheses supporting specific roles for these neurotransmitters in schizophrenia. The overall goal of this application is to investigate and characterize the cellular pharmacology of presynaptic and postsynaptic mGLURs at pharmacologically and electrically isolated native excitatory and inhibitory synapses, while determining their role in an animal model of the GLU-NMDA Receptor Hypofunction (NRF)-hypothesis of schizophrenia. Intracellular recordings from a brain slice preparation of the dorsolateral septal nucleus (DLSN) will be used to investigate the cellular actions of specific mGLUR agonists and antagonists for the three GROUPs of mGLURs (I, II, III).
The specific aims of this application will determine: (1) the mechanisms by which an endogenous excitatory transmitter, GLU, regulates its own release via specific presynaptic mGLURs (autoreceptors); (2) how activation of mGLURs on gamma-aminobutyric acid (GABA)ergic terminals regulates the release of GABA via other types of presynaptic mGLURs (heteroreceptors); and (3) how activation of a postsynaptic mGLUR may potentiate the NMDA component of an excitatory synaptic terminal, a component suggested to be depressed in the NRF hypothesis of schizophrenia. Finally, mGLUR mechanisms in control animals will be compared with brains of animal models of schizophrenia from rats treated chronically with PCP, a drug known to induce behavioral changes similar to those seen in patients with schizophrenia. The DLSN slice preparation has been chosen to study since DLSN contains the relevant neuronal circuitry implicated in the GLU-NRF-hypothesis of schizophrenia as proposed by Coyle (Fig. 3) and the DLSN expresses multiple types of mGLURs. Furthermore, no comparable circuitry is available in a more reduced preparation. These experiments will enhance our understanding of the mechanisms of normal synaptic transmission and transmission in an animal model of schizophrenia. Together these data may provide evidence for the use of a novel group of drugs in the treatment of schizophrenia.
| Yu, B; Wang, C; Liu, J et al. (2002) Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors. Neuroscience 113:1-10 |
| Neugebauer, V; Zinebi, F; Russell, R et al. (2000) Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. J Neurophysiol 84:759-70 |
