Acute regulation of synaptic NMDA receptor content in hippocampal neurons

Abstract

Hippocampal-dependent learning, which is required for forming fact-based, declarative memories, involves changing the physical and functional characteristics of connections between neurons, called synapses. This process of “synaptic plasticity” is mediated by the N-methyl-D-aspartate receptor (NMDAR). NMDARs are ionotropic glutamate receptors found within synapses and when activated, initiate intracellular signaling cascades that result in plasticity. Historically, NMDARs have been considered static components of synapses. More recent evidence, however, overturns this dictum to reveal that NMDARs are dynamic, and regulated by many factors including receptor subunit composition and the previous activity of the neuron. In this thesis, I describe two means by which hippocampal neurons can regulate synaptic NMDAR content: (1) The number and type of synaptic NMDARs can be regulated by a secreted glycoprotein, Wnt5a. Wnt5a increases the delivery of NMDARs into synapses from intracellular compartments by triggering a signaling cascade involving membrane depolarization and release of calcium from internal stores. (2) NMDARs can move laterally on the neuron surface between synaptic and extrasynaptic compartments in an activity-dependent, calcium-independent process. The ability of neurons to finely tune their synaptic NMDAR content provides a means for optimizing the ability of a synapse to undergo plasticity given a certain set of conditions. The two mechanisms described here may provide potential platforms on which to develop novel therapeutics to treat neurodegenerative or neuropsychiatric disorders where synaptic plasticity has been compromised.