Subsaturation of the N-methyl-D-aspartate receptor glycine site allows the regulation of bursting activity in juvenile rat nigral dopamine neurons.

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA-related behaviours via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release, but the glycine site level of occupancy of these receptors during basal action potential-dependent activity is not known for SNc DA neurons. We explored NMDAR-dependent signals during exogenous applications of co-agonists in midbrain slices from juvenile rats. We found that both glycine and D-serine strengthened the NMDAR-dependent component of excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviourally relevant burst firing was more sensitive to exogenous D-serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co-agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co-agonists may be important for nigral information processing and downstream motor-related behaviour.

Differential Somatic Ca2+ Channel Profile in Midbrain Dopaminergic Neurons.

UNLABELLED: Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia nigra pars compacta (SNc), the pacemaking relies more on Ca(2+) channels and that the density of L-type Ca(2+) channels is higher in these DA neurons than in those located in the ventral tegmental area (VTA). This might lead to a higher Ca(2+) load in SNc DA neurons and explain their higher susceptibility to degeneration. However, direct evidence for this hypothesis is lacking. We found that the L-type current and channel density are indeed higher in the somata of rat SNc DA neurons and that this current undergoes less inactivation in this region. Nonstationary fluctuation analysis measurements showed a much higher number of L-type channels in the soma of SNc DA neurons, as well as a smaller single-channel conductance, pointing to a possible different molecular identity of L-type channels in DA neurons from the two areas. A major consequence of this is that pacemaking and, even more so, bursting are associated with a larger Ca(2+) entry through L-type channels in SNc DA neurons than in their VTA counterparts. Our results establish a molecular and functional difference between two populations of midbrain DA neurons that may contribute to their differential sensitivity to neurodegeneration. SIGNIFICANCE STATEMENT: Dopamine neurons from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are involved in various brain functions, such as movement initiation and goal directed behavior, respectively. This work shows that, although both neurons fire in a similar regular and slow pacemaker mode, this firing activity is supported by different calcium channel landscapes. Indeed, the L-type calcium current is larger in the soma of dopamine neurons of the SNc, leading to a higher charge transfer through L-type channels during pacemaking and bursting. Therefore, these neurons may be physiologically exposed to a larger stress than their neighbors from the VTA.