We demonstrate a rapid and complex effect of N-methyl-d-aspartate receptor (NMDAR) activation on synaptic protein synthesis in the superior colliculi of young rats. Within minutes of receptor activation, translation of alpha Ca2+/calmodulin dependent kinase II (alphaCamK II) was increased, whereas total protein synthesis was reduced. NMDAR activation also increased phosphorylation of eukaryotic elongation factor 2 (eEF2), a process known to inhibit protein translation by reducing peptide chain elongation. Low doses of cycloheximide, which reduce elongation rate independently of eEF2 phosphorylation, decreased overall protein synthesis but increased alphaCaMK II synthesis. These observations suggest that regulation of peptide elongation via eEF2 phosphorylation can link NMDAR activation to local increases in the synthesis of specific proteins during activity-dependent synaptic change.

The RhoA (Rho) GTPase is a master regulator of dendrite morphogenesis. Rho activation in developing neurons slows dendrite branch dynamics, yielding smaller, less branched dendrite arbors. Constitutive activation of Rho in mature neurons causes dendritic spine loss and dendritic regression, indicating that Rho can affect dendritic structure and function even after dendrites have developed. However, it is unclear whether and how endogenous Rho modulates dendrite and synapse morphology after dendrite arbor development has occurred. We demonstrate that a Rho inhibitory pathway involving the Arg tyrosine kinase and p190RhoGAP is essential for synapse and dendrite stability during late postnatal development. Hippocampal CA1 pyramidal dendrites develop normally in arg Ϫ/Ϫ mice, reaching their mature size by postnatal day 21 (P21). However, dendritic spines do not undergo the normal morphological maturation in these mice, leading to a loss of hippocampal synapses and dendritic branches by P42. Coincident with this synapse and dendrite loss, arg Ϫ/Ϫ mice exhibit progressive deficits in a hippocampus-dependent object recognition behavioral task. p190RhoGAP localizes to dendritic spines, and its activity is reduced in arg Ϫ/Ϫ hippocampus, leading to increased Rho activity. Although mutations in p190rhogap enhance dendritic regression resulting from decreased Arg levels, reducing gene dosage of the Rho effector ROCKII can suppress the dendritic regression observed in arg Ϫ/Ϫ mice. Together, these data indicate that signaling through Arg and p190RhoGAP acts late during synaptic refinement to promote dendritic spine maturation and synapse/dendrite stability by attenuating synaptic Rho activity.

The NMDA subtype of glutamate receptor is hypothesized to mediate synaptic competition in the developing brain by stabilizing converging synapses that have correlated activity patterns. Disruption of NMDA receptor function during development interferes with synapse elimination and sensory map formation. Moreover, many studies indicate that NMDA receptor function is high during times of synaptic rearrangement. In this review, a corollary of the NMDA receptor hypothesis for activity-dependent synapse stabilization is proposed. As developing inputs increase in number and strength, the increasing excitatory synaptic activity in young neurons should lead to increases in postsynaptic Ca2+ influx through NMDA receptors. This Ca2+ flux is postulated to trigger a feedback system that changes the subunit composition of the NMDA receptor complex so that less Ca2+ enters postsynaptic cells upon NMDA receptor activation. Changes in NMDA receptor effectiveness resulting from manipulations of activity are consistent with the idea that NMDA receptor function is under the control of activity. This postulate of activity-dependent control of NMDA receptor expression has implications for the control of brain plasticity. If particular combinations of NMDA receptor subunits typically expressed in young animals are better than adult receptor types at maintaining synapses in regions where they are not well correlated with other inputs, then expression of these juvenile subunit combinations could facilitate synaptic rearrangements in the mature brain after the normal end of synaptic plasticity. Thus, understanding the regulation of NMDA receptor function during development could provide a novel approach to restructuring circuitry in the adult brain to compensate for damage produced by trauma or disease.

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N -methyl- d -aspartate receptor (NMDAR) activation has been implicated in forms of synaptic plasticity involving long-term changes in neuronal structure, function, or protein expression. Transcriptional alterations have been correlated with NMDAR-mediated synaptic plasticity, but the problem of rapidly targeting new proteins to particular synapses is unsolved. One potential solution is synapse-specific protein translation, which is suggested by dendritic localization of numerous transcripts and subsynaptic polyribosomes. We report here a mechanism by which NMDAR activation at synapses may control this protein synthetic machinery. In intact tadpole tecta, NMDAR activation leads to phosphorylation of a subset of proteins, one of which we now identify as the eukaryotic translation elongation factor 2 (eEF2). Phosphorylation of eEF2 halts protein synthesis and may prepare cells to translate a new set of mRNAs. We show that NMDAR activation-induced eEF2 phosphorylation is widespread in tadpole tecta. In contrast, in adult tecta, where synaptic plasticity is reduced, this phosphorylation is restricted to short dendritic regions that process binocular information. Biochemical and anatomical evidence shows that this NMDAR activation-induced eEF2 phosphorylation is localized to subsynaptic sites. Moreover, eEF2 phosphorylation is induced by visual stimulation, and NMDAR blockade before stimulation eliminates this effect. Thus, NMDAR activation, which is known to mediate synaptic changes in the developing frog, could produce local postsynaptic alterations in protein synthesis by inducing eEF2 phosphorylation.