Synaptic release of glutamate coincident with postsynaptic depolarization allows NMDA receptors to mediate a slow, Ca2+-permeable component of the excitatory synaptic current. The resulting influx of Ca2+ can trigger changes in synaptic strength that have been proposed as a cellular correlate of learning and memory. Reduction of NMDA receptor function blocks many forms of synaptic plasticity, and enhancement of the GluN2B subunit expression enhances synaptic plasticity. For these reasons, allosteric potentiators of the GluN2B subunit have long been predicted to act as cognitive enhancers, with potential clinical utility in a wide range of conditions including Alzheimer's disease, post-injury motor learning, and schizophrenia. Work supported by the previous funding cycle allowed us to define the structural determinants and mechanism of action of 2 new classes of negative allosteric NMDA receptor modulators and 3 new classes of allosteric potentiators that are highly selective for NMDA receptors containing the GluN2C or GluN2C/D subunits. During the previous funding cycle, we also identified for the first time several drug-like GluN2B allosteric potentiators. The site and mechanism of action of GluN2B potentiation is distinct from that observed for GluN2C/D potentiators. Potentiation is absent when the alternatively spliced exon5 of GluN1 is included in the amino terminal domain, and these new compounds show strong potentiation (>5-fold) of responses to submaximal agonist responses in part due to allosteric enhancement of glutamate and/or glycine potency. These GluN2B potentiators do not act at any known modulator binding site, and thus break new ground in terms of NMDA receptor regulation. We propose 3 experiments that will advance our understanding of NMDA receptor gating, the site and mechanism of action of these modulators, the role of GluN2B in synaptic plasticity, and the effects of GluN2B potentiation in learning/memory.
Aim 1 : What is the mechanism of action of GluN2B potentiation? We will use whole cell voltage clamp and single channel recordings from recombinant and neuronal GluN2B-containing NMDA receptors to elucidate the mechanism by which representative members of two classes of compounds potentiate receptor function.
Aim 2 : What are the structural determinants of GluN2B potentiators? We will utilize a chimeric strategy and mutagenesis through of preM1/M1 regions in GluN1 and GluN2B to identify the structural determinants of action. We have developed azide and benzophenone photoaffinity labels that are active and should covalently label residues near the binding pocket of His-tagged GluN1 and GluN2 subunits.
Aim 3 : Does potentiation of GluN2B function alter synaptic plasticity? We will assess the ability of GluN2B potentiation to shift the threshold necessary to induce plasticit (LTP, LTD) in hippocampal slices.
Aim 4 : Does potentiation of GluN2B function alter learning and memory in vivo? We will assess in vivo the effects on learning for the class of GluN2B allosteric potentiator that is brain permeable.
NMDA receptors, which are comprised of GluN1 and GluN2 subunits, mediate communication between neurons and thus play an important role in brain function and neurological diseases. Although potentiators and inhibitors selective for each of the four GluN2 subunits (A-D) have been proposed as useful therapeutic agents, subunit-selective inhibitors only exist for GluN2B (ifenprodil) and more recently GluN2A (TCN201). Work completed during the previous funding cycle (2009-2013), led to the first description of potent and subunit-selective GluN2C/D modulators and also revealed a novel class of compounds that selectively potentiate GluN2B. We will determine the mechanisms and effects of this new class of subunit-selective potentiators, which provide the first opportunity to test whether GluN2B potentiation could be useful for cognitive enhancement, memory loss, schizophrenia, and other health problems.
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