Regulation of spine morphology and spine density by NMDA receptor signaling in vivo

Abstract

Dendritic spines are the major sites of excitatory synaptic transmission in the CNS, and their size and density influence the functioning of neuronal circuits. Here we report that NMDA receptor signaling plays a critical role in regulating spine size and density in the developing cortex. Genetic deletion of the NR1 subunit of the NMDA receptor in the cortex leads to a decrease in spine density and an increase in spine head size in cortical layer 2/3 pyramidal neurons. This process is accompanied by an increase in the presynaptic axon bouton volume and the postsynaptic density area, as well as an increase in the miniature excitatory postsynaptic current amplitude and frequency. These observations indicate that NMDA receptors regulate synapse structure and function in the developing cortex.cortex ͉ development ͉ synapse D endritic spines are bulbous membrane protrusions that form the postsynaptic specializations of the vast majority of excitatory synapses in the CNS (1-3). During the first postnatal week, highly motile and short-lived dendritic filopodia are abundant on cortical pyramidal neurons (4). These actin-rich protrusions make immature synapses along their length or tip (5). The dendritic spines that are present during the first two postnatal weeks display an immature morphology (5), and the spine head is highly motile, with protrusions extending and retracting from the head (6). After the second postnatal week, the spine density increases, and spines attain a mature morphology with bulbous heads similar to that seen in the adult (7). Dendritic spines are sites of excitatory synaptic transmission, and their structure and density are important measures of synaptic function.An important feature of dendritic spines is that their volume and density can be dynamically regulated. Stimuli that induce long-term potentiation (LTP) and long-term depression in hippocampal slices lead to rapid changes in spine volume by activation of NMDA receptors (8-10). Several lines of evidence suggest that NMDA receptor signaling might influence spine volume by recruitment of AMPA receptors (AMPARs). Immature synapses in the CNS have a low AMPAR:NMDA receptor (NMDAR) ratio and gradually acquire AMPARs during development (11,12). The increase in the AMPAR:NMDAR ratio at synapses during development is thought to be mediated by NMDAR-induced recruitment of AMPARs (13-16). This increase in surface AMPARs could influence spine volume because it has been reported that overexpression of the GluR2 AMPAR subunit in hippocampal cultures leads to an increase in spine size (17). NMDAR signaling also has been implicated in regulating spine density. In hippocampal slices, LTP-inducing stimuli or glutamate application leads to the rapid induction of new spines/filopodia, which is blocked by NMDAR antagonists (18,19).These observations suggest a model in which NMDARs recruit AMPARs to developing synapses, which drives spine growth and maturation. This model predicts that loss of NMDARs should lead to smaller AMPA currents and smaller spines. Her...

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

“…Furthermore, acute NMDA receptor antagonism with ketamine has recently been shown to increase spine density, at least transiently, in the cortex (35). In the reports of cell-specific, genetic deletion of NMDA receptors, temporal differences in the developmental stage of Cre expression may explain the variable effects on synapse number (10,11,13,14). With pharmacological studies, it is conceivable that transient and sustained NMDA receptor blockade have opposite effects on synapse function and ultimately on spine density.…”

“…At the molecular level, NMDA-type glutamate receptors have long been appreciated for their role in the formation and maintenance of glutamatergic synapses (7), and as mediators of synaptic plasticity (8). Several studies have shown a positive correlation between NMDA receptor activity and spine density (9)(10)(11)(12), with notable exceptions (13,14). However, the molecular mechanisms by which NMDA receptors regulate spine density remain to be fully elucidated.…”

NMDA receptors inhibit synapse unsilencing during brain development

“…However, patterning in the somatosensory pathway is completely disrupted, an effect observed in the barrel field even when the NR1 deletion is limited to cortex but not thalamus (5). Additionally, cortex-specific NR1 or NR2B deletion has been shown to decrease spine density and alter synapse function in layer 2/3 barrel neurons (21,22). Finally, a recent study used RNAi to knock down NR1 expression in hippocampal pyramidal neurons in organotypic slices and found that compromised NMDA receptor expression decreased net AMPA receptor-mediated input (23).…”

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

“…Receptors for glutamate, especially NMDA receptors, are intimately involved in the early formation of the central nervous system (CNS), being required for neuronal migration (Komuro and Rakic, 1993;Behar et al, 1999), axonal and neurite growth in the foetus and postnatally, neurite extension and branching (Heng et al 1999;Cuppini et al 1999;Rajan and Cline 1998), spine formation and stability (Alvarez et al, 2007;Ultanir et al, 2007), the formation and stability of synapses (Colonnese et al, 2005) and neuronal plasticity (Fagiolini et al,. 2003;Iwasato et al, 2000).…”

“…NMDA receptors have well-established roles in the early migration of neural precursors, neuritogenesis, axonal guidance, spine formation and synapse formation (Colonnese et al, 2005;Komuro and Rakic, 1993;Behar et al, 1999;Heng et al, 1999;Cuppini et al, 1999;Rajan and Cline, 1998;Alvarez et al, 2007;Ultanir et al, 2007). Furthermore, NMDAR contribute to the programmed cell death which shapes the early nervous system by eliminating a proportion of neurons.…”