Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

Abstract

support-information-section).

Extrasynaptic NMDA receptors bidirectionally modulate intrinsic excitability of inhibitory neurons

“…Previous studies have suggested that NMDARs may contribute to the excitability of inhibitory neurons [34][35][36][37] . To test whether this is the case, we examined the effect of bath applied NMDAR modulators on genetically identified GABAergic neurons in PFC slices from GAD-67 GFP mice.…”

“…This strategy is especially useful for in vitro analysis since it is likely that the level of NMDAR activation is low in brain slices compared to in vivo. Although a large number of NMDAR-PAMs have been developed 37 , for treating diseases with reduced inhibitory neuron activity NMDAR-PAMs that selectively enhance the activity of inhibitory neurons (such as GNE-8324 and M-8324) (Hackos, 2016;Yao, 2018;Deng, 2020) will likely be more useful by avoiding potential counteraction and excitotoxicity due to enhanced activation of excitatory neurons (Hanson, et al, 2020).…”

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches

“…Clearly, there is great functional significance associated with normally expected developmental regulation of the switch to an increased ratio of GluN2A-containing NMDA receptors to GluN2B containing receptors; expression of GluN2A subunits increases after birth and their content exceeds that of GluN2B subunits by adulthood. Thus, in neuropsychiatric conditions associated with imbalance in activation mediated by functional GluN2A- (e.g., relatively lower) and GluN2B- (e.g., relatively higher) containing NMDA receptors, there is therapeutic interest in developing subtype selective (e.g., GluN2A) positive allosteric modulators to address at least some of the pathological consequences resulting from imbalance of functional GluN2 receptor subtypes [ 9 , 11 , 12 ].…”

“…Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors [ 9 , 10 , 11 , 12 ]. The challenges are to understand the implications and impact of these expressed individual sequence variants on alterations of: conductance and gating properties of the ion channel and binding properties of the glutamate and glycine/D-serine orthosteric binding sites; pharmacological properties of allosteric modulatory sites [ 13 ].…”

“…This Review considers diverse examples of “illness” genes, their pathogenic effects on NMDA receptor activation ( Table 1 ) and the results of studies of impaired sociability in mouse models, including “proof of principle/proof of concept” experiments exploring NMDA receptor agonist interventions. Moreover, we will provide discussion on the development of promising representative PAMs, which serve as support and models for developing an inventory of PAMs and NAMs for translational therapeutic intervention and provide an update of other developmental efforts in this area [ 9 ]. Importantly, there is a moral imperative to develop newer medication strategies that will complement other essential components of individualized, multimodal treatment plans because current clinical outcomes of patients with ASD are less than optimal and both patients and “unaffected” neurotypical family members experience much morbidity.…”