Mechanisms regulating spill‐over of synaptic glutamate to extrasynaptic NMDA receptors in mouse substantia nigra dopaminergic neurons

Abstract

N-Methyl-D-aspartate glutamate receptors (NMDARs) contribute to neural development, plasticity and survival, but they are also linked with neurodegeneration. NMDARs at synapses are activated by coincident glutamate release and depolarization. NMDARs distal to synapses can sometimes be recruited by 'spill-over' of glutamate during high-frequency synaptic stimulation or when glutamate uptake is compromised, and this influences the shape of NMDAR-mediated postsynaptic responses. In substantia nigra dopamine neurons, activation of NMDARs beyond the synapse during different frequencies of presynaptic stimulation has not been explored, even though excitatory afferents from the subthalamic nucleus show a range of firing frequencies, and these frequencies change in human and experimental Parkinson's disease. This study reports that high-frequency stimulation (80 Hz/ 200 ms) evoked NMDAR-excitatory postsynaptic currents (EPSCs) that were larger and longer lasting than those evoked by single stimuli at low frequency (0.1 Hz). MK-801, which irreversibly blocked NMDAR-EPSCs activated during 0.1-Hz stimulation, left a proportion of NMDAR-EPSCs that could be activated by 80-Hz stimulation and that may represent activity of NMDARs distal to synapses. TBOA, which blocks glutamate transporters, significantly increased NMDAR-EPSCs in response to 80-Hz stimulation, particularly when metabotropic glutamate receptors (mGluRs) were also blocked, indicating that recruitment of NMDARs distal to synapses is regulated by glutamate transporters and mGluRs. These regulatory mechanisms may be essential in the substantia nigra for restricting glutamate diffusion from synaptic sites and keeping NMDAR-EPSCs in dopamine neurons relatively small and fast. Failure of glutamate transporters may contribute to the declining health of dopamine neurons during pathological conditions.

Thresholding of sensory inputs by extrasynaptic glutamate receptors in olfactory bulb glomeruli

“…1B2 ). With such an arrangement, glutamate transients sufficient to activate glutamate receptors may require the accumulation of glutamate generated across multiple spikes (Asztely et al, 1997; Carter and Regehr, 2000; Clark and Cull-Candy, 2002; Chalifoux and Carter, 2011; Coddington et al, 2013; Nahir and Jahr, 2013; Wild et al, 2015). We sought to test one prediction of the distant-receptor model, which is that pharmacological blockade of glutamate transporters aligning the extrasynaptic space should enhance extrasynaptic currents induced by spike bursts (Asztely et al, 1997).…”

“…As a means of signaling between neurons, glutamatergic activation of extrasynaptic AMPA and NMDA receptors has been reported in a wide range of circuits (Asztely et al, 1997; Isaacson, 1999; Carter and Regher, 2000; DiGregorio et al, 2002; DeVries et al, 2006; Szapiro and Barbour, 2007; Chalifoux and Carter, 2011; Coddington et al, 2013; Wild et al, 2015). The extrasynaptic, spillover-mediated transmission that we have described between eTCs and MCs however stands out, first, because it is the primary mode of signaling between eTCs and MCs.…”

“…Extrasynaptic transmission, which is likely promoted by confined spaces intrinsic to glomeruli (Rossi et al, 1995; Kinney et al, 1997; Chao et al, 1997; Kasowski et al, 1999), could provide a potentially powerful tool for generating an intraglomerular threshold. In contrast to synaptic glutamate receptors that sense a high glutamate concentration even when a presynaptic cell fires single spikes (Clements et al, 1992), activation of extrasynaptic glutamate receptors generally requires coincident activation of many nearby axons or trains of action potentials to enable accumulation of glutamate at receptor sites (Asztely et al, 1997; Carter and Regehr, 2000; Clark and Cull-Candy, 2002; Chalifoux and Carter, 2011; Coddington et al, 2013; Nahir and Jahr, 2013; Wild et al, 2015). Such dynamics in extrasynaptic glutamate could contribute to an E/I balance for MCs/TCs that favors inhibition over excitation in the presence of a weak stimulus that drives few eTC spikes (e.g., a low-affinity odor) but a much more favorable E/I balance with a strong stimulus.…”

VTA dopamine neuron plasticity – the unusual suspects

“…A similar adaptation in the VTA could greatly impact signalling onto DA neurons. In support of this hypothesis, pharmacological blockade of GLT-1 and GLAST increases activation of extrasynaptic NMDARs in DA neurons (Wild et al, 2015), and disrupting the orthologue of GLT-1 (glt-1-6) in C. elegans produces DA neuron hyperexcitability (Hardaway et al, 2015). It is conceivable, then, that certain stimulus-triggered adaptations within the VTA may be resulting from, or at least enhanced by, a reduction in astrocyte uptake of glutamate.…”

“…In addition to modulating the time course of synaptic glutamate receptor activation, astrocyte ensheathment of synapses, or lack thereof, can determine the degree to which glutamate spillover from synapses can activate pre-and extrasynaptic glutamate receptors (Oliet et al, 2001;Oliet & Bonfardin, 2010;Wild et al, 2015). This aspect of astrocyte biology merits greater scrutiny within the VTA, as studies in other regions have shown that both the structure of astrocyte processes and the level of glutamate transporters present on these processes are altered by stimuli that impact signalling in the VTA.…”