Changes of glutamatergic control of striatal acetylcholine release in experimental parkinsonism

The cholinergic interneurones represent less than 2 % of the total striatal cell population. These giant aspiny neurons display an extensive dendritic and axonal network receiving massive inputs from several neurotransmitter systems, and therefore play a fundamental role in the integration and transfer of information between afferent and efferent striatal pathways (Kawaguchi et al., 1995). In particular, the cholinergic interneurones integrate dopaminergic inputs originating in substantia nigra and glutamatergic inputs arising mainly from the cerebral cortex and from the parafascicular nucleus of the thalamus (Consolo et al., 1996; Baldi et al.,1995). Glutamatergic inputs are conveyed by different glutamate (Glu) receptor subtypes, namely ionotropic (iGlu; NMDA and non-NMDA subtypes) and metabotropic (mGlu; group I-III subtypes) which are localized on the membranes of striatal cholinergic interneurones (Tallaksen-Greene et al., 1994; Bernard et al., 1997 Testa et al., 1994; Pisani et al., 2002; Bell et al., 2002). Firing activity and neurosecretion of cholinergic interneurones are affected depending upon which Glu receptor subtype is activated, iGlu or group-I mGlu receptors being facilitatory (Ruzicka and Jhamandas 1993; Di Chiara et al., 1994; Kawaguchi et al., 1995; Calabresi et al., 1998; Morari et al., 1998) and group-II mGlu receptors inhibitory (Pisani et al., 2002; Marti et al., 2001; 2003). Since striatal cholinergic interneurones play a crucial role in the modulation of striatofugal pathways and motor behavior (Di Chiara et al., 1994; Kaneko et al., 2000), much effort has been put into the understanding of the physiopathological mechanisms involved, both at the cellular and circuitry level. In particular, since Glu is the driving force of striatal cholinergic interneurones, it is relevant to investigate whether changes of cholinergic transmission following degeneration of the nigrostriatal dopaminergic pathway during Parkinson’s disease (PD; Schwarting and Huston, 1996) are associated with changes in the glutamatergic modulation. Therefore, the studies carried out in our laboratories during the last few years were aimed to investigate the effects of selective NMDA, non-NMDA and mGlu receptor agonists and antagonists on endogenous ACh release from rat striatal slices and synaptosomes, and to determine whether iGlu and mGlu receptor mediated regulation of ACh release undergoes plastic changes following disruption of the nigrostriatal pathway with 6-hydroxydopamine (6-OHDA), one of the most established models of PD