NR2A Subunit Expression Shortens NMDA Receptor Synaptic Currents in Developing Neocortex

Abstract

NMDA receptors play important roles in learning and memory and in sculpting neural connections during development. After the period of peak cortical plasticity, NMDA receptor-mediated EPSCs (NMDAR EPSCs) decrease in duration. A likely mechanism for this change in NMDA receptor properties is the molecular alteration of NMDA receptor structure by regulation of NMDA receptor subunit gene expression. The four modulatory NMDAR2A-D (NR2A-D) NMDA receptor subunits are known to alter NMDA receptor properties, and the expression of these subunits is regulated developmentally. It is unclear, however, how the four NR2 subunits are expressed in individual neurons and which NR2 subunits are important to the regulation of NMDA receptor properties during development in vivo. Analysis of NR2 subunit gene expression in single characterized neurons of postnatal neocortex revealed that cells expressing NR2A subunit mRNA had faster NMDAR EPSCs than cells not expressing this subunit, regardless of postnatal age. Expression of NR2A subunit mRNA in cortical neurons at even low levels seemed sufficient to alter the NMDA receptor time course. The proportion of cells expressing NR2A and displaying fast NMDAR EPSCs increased developmentally, thus providing a molecular basis for the developmental change in mean NMDAR EPSC duration.

Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex

“…Previous studies demonstrated that dark rearing or 5 d of visual deprivation in juvenile rats decreases the relative expression of NR2A-to NR2B-containing NMDARs, resulting in longer NMDAR-mediated currents (Carmignoto and Vicini, 1992;Flint et al, 1997;Philpot et al, 2001a). We found that a similar process occurs in mice.…”

“…NR1, NR2A, and NR2B subunits predominate in the postnatal visual cortex, and during development the ratio of NR2A-to NR2B-containing NMDARs increases (Quinlan et al, 1999a,b;Roberts and Ramoa, 1999). Because NR2A-containing NMDARs possess shorter current durations than NR2B-containing receptors, NMDAR-mediated current durations shorten over development (Carmignoto and Vicini, 1992;Hestrin, 1992;Monyer et al, 1992;Priestley et al, 1995;Flint et al, 1997;Vicini et al, 1998). The developmental increase in NR2A in the visual cortex is experience-dependent, because dark rearing delays the increase in NR2A in the visual cortex (Nase et al, 1999;Quinlan et al, 1999b).…”

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…The delayed maturation of postsynaptic G protein mediated GABA B inhibition also contributes to increased brain excitability [21]. The prolonged NMDA-mediated excitatory postsynaptic currents (EPSCs) in immature versus adult neurons will also promote the generation of network driven events [22].…”

Activity-Dependent Regulation of NMDAR1 Immunoreactivity in the Developing Visual Cortex

“…For instance, in rat visual cortex, the duration of the NMDA-mediated EPSC decreases during development, and dark-rearing prevents this decrease (Carmignoto and Vicini, 1992). This decrease could be caused by a shift in NMDA receptor subunit expression (Sheng et al, 1994;Flint et al, 1997). Another possibility, not mutually exclusive, is that the levels of NMDA receptors themselves change during development in association with periods of cortical plasticity.…”

“…Our results suggest that the physiological alterations that occur during darkrearing do not result from major changes in the amount of NMDAR1 protein. However, NMDA receptor subunit composition (Sheng et al, 1994;Flint et al, 1997) and/or phosphorylation state (Roche et al, 1994;Tingley et al, 1997) may change with dark-rearing, because both have also been shown to affect channel function.…”