Benchmark IV Progressing Nicely: Rational Pharmacotherapy May Address Cognitive Decline in Epilepsy.

Commentary NMDA-type glutamate receptors (NMDARs) have been front and center in synaptic plasticity (1) since they were first distinguished from other glutamate receptors pharmacologically in the 1980s. NMDARs are typically assembled from GluN subunits (GluN1, 2A-D) as tetrameric heteromers containing two GluN1 subunits and two, not necessarily the same, GluN2 subunits (2). Subunit " guidelines " have been proposed where GluN2A assemblies mediate long-term potentiation (LTP) and GluN2B assemblies mediate long-term depression (LTD). These are guidelines, as supporting evidence (3) is often contradictory (4) and dependent on the experimental details such as concentrations of antagonists used, techniques and, importantly , developmental age (5). Recent work highlights that the location of particular subunit assemblies, that is, synaptic versus extrasynaptic, is equally important (6). This distinction is rather important as activation of extrasynaptic versus syn-aptic NMDARs has been distinguished as mediating neuronal death versus survival (7). This specific, localized role and the mechanistic details in diseases has lately begun to emerge, for instance in Huntington disease (8). Synaptic activation of NMDARs seems straightforward: glutamate is released from presynaptic terminals and diffuses to nearby receptors. Extrasynaptic receptors are activated by glutamate that spills over from the cleft or is not taken up by transporters on glia or neurons. However, NMDARs can also be activated by glutamate released from astrocytes (9). Further, NMDARs require glycine or D-serine as a co-agonist with glu-tamate in order to fully gate ionic currents; the efficacy of glu-tamate and glycine depend on the specific GluN2 assembly; GluN2B assemblies are more sensitive to both glutamate and glycine (10). The source and role of glycine and D-serine has recently been probed to suggest that astrocytically released D-serine is important for synaptic NMDARs and necessary for LTP, while glycine is important for extrasynaptic NMDARs and LTD (6). Again, these are not rules, only guidelines, as there is no clear boundary between the synapse, perisynapse, and extrasynapse. The ambient concentrations of glycine or D-serine are not saturating and can be modulated dynamically in order to influence NMDAR function and plasticity (11). The means to separate NMDARs pharmacologically is limited by the tools available. While NR2B relatively selective antagonists are available (such as ifenprodil and RO25-6981), antagonists for differentiating mixed assemblies (e.g., NR2A/NR2B) are lacking (12). Thus, it seems logical that the role of NMDARs in mediating the cognitive deficits (13) associated with epilepsy should be probed. The authors utilized the pilocarpine model of …