Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive

Glutamate represents the major excitatory neurotransmitter in the mammalian brain (Hayashi, 1952). Its actions are mediated by a number of receptor types, which are classified as metabotropic and ionotropic. While metabotropic glutamate receptors transduce ligand binding to intracellular signalling cascades and may indirectly modulate ion channel function, ionotropic receptors are glutamate-gated cation channels. N-Methyl-d-aspartate (NMDA) channels, in particular, are highly permeable to Ca2+ ions (MacDermott et al. 1986) and behave as non-linear conductors due to the presence of a Mg2+ block at hyperpolarized potentials (Nowak et al. 1984; Mayer et al. 1989). The ability of the NMDA receptor to act as a glutamate-gated Ca2+ channel has been proposed to result in concomitant electrical and biochemical effects of glutamate on neurones. Thus, the NMDA receptor has been linked to a wide range of physiological processes, including synaptic transmission and integration, synaptic plasticity, and membrane potential oscillations, as well as pathological manifestations, such as epilepsy and neuronal death (Collingridge & Watkins, 1994; Schmidt et al. 1998). Activation of the NMDA receptor produces oscillatory activity in a wide variety of spinal and supraspinal neuronal systems (Hochman et al. 1994a,b; Kim & Chandler, 1995; Flint & Connors, 1996; Kiehn et al. 1996; Guertin & Hounsgaard, 1998; Moore et al. 1999; Prime et al. 1999; Tresch & Kiehn, 2000). It has been postulated that such oscillations may participate in the generation of physiological rhythmic neuronal output and associated behaviour (Grillner & Matsushima, 1991; Schmidt et al. 1998). Moreover, NMDA receptor-induced oscillations have been associated with the onset of convulsions (Palmer et al. 1993). Therefore, the NMDA receptor provides a powerful link between glutamatergic input and the rhythmic modulation of neuronal function and behaviour. The inferior olive of the medulla oblongata is a highly rhythmic nucleus that plays a powerful role in the regulation of movement. Its rhythmicity is conferred by a set of ionic currents (Llinas & Yarom, 1981A,b, 1986; Benardo & Foster, 1986; Yarom & Llinas, 1987; Lampl & Yarom, 1997; Bal & McCormick, 1997) and electrical coupling (Llinas et al. 1974), and it directly influences movement due to its monosynaptic connection with Purkinje cells of the cerebellar cortex (Eccles et al. 1966). Olivary neurones manifest oscillations in membrane potential that are subthreshold for spiking (Llinas & Yarom, 1986; Benardo & Foster, 1986) and which are mediated by the low-threshold calcium current, IT (Lampl & Yarom, 1997). The subthreshold oscillations have been postulated to be functionally related to the coordination of movement (Welsh et al. 1995) and, in the extreme, to the manifestation of rhythmic myoclonus (Welsh et al. 1998). The role that NMDA receptor currents may play in mediating oscillatory activity in olivary neurones remains unknown. Two recently reported observations suggest that the NMDA receptor may be involved in the generation of rhythmic activity of the inferior olive. First, dizocilpine (MK-801), a non-competitive antagonist of the NMDA receptor, blocked both the tremorigenic and amnestic effects of harmaline (Du & Harvey, 1997), actions that are mediated by effects on the inferior olive (de Montigny & Lamarre, 1973; Llinas & Volkind, 1973; Llinas & Yarom, 1986; Welsh, 1998). Second, harmaline competed with MK-801 for binding to the NMDA receptor (Du et al. 1997). These findings suggest that NMDA receptors may be central in olivary function under both physiological and pathological conditions. To address the question of NMDA receptor involvement in olivary oscillations, we studied the effects of NMDA receptor blockade and activation on inferior olivary neurones in vitro using intracellular recordings. Our findings indicate that the NMDA receptor enhances oscillatory activity in olivary neurones. Some of the data have been published in abstract form (Placantonakis & Welsh, 1999).