Regulation of N-methyl-D-aspartate (NMDA) receptor function during the rearrangement of developing neuronal connections

Department of Biology, Yale University, New Haven, CT 06511.
Progress in brain research (Impact Factor: 2.83). 02/1994; 102:277-85. DOI: 10.1016/S0079-6123(08)60546-4
Source: PubMed


There is evidence from a number of studies that the molecular and biophysical properties of NMDA receptors are altered during normal development. A temporal correlation with changes in NMDA receptor efficacy and periods of synaptic plasticity has been demonstrated in several systems, suggesting that NMDA receptors have a critical function in determining periods of synaptic plasticity. Data from our laboratory demonstrate reduced NMDA sensitivity of the tectal evoked potential following chronic application of NMDA to the tadpole tectum, a treatment that may mimic a naturally occurring mechanism for limiting neuronal plasticity to certain stages of development. Our analysis of the expression pattern of mRNA coding for various glutamate receptor subunits in the rat retinocollicular system establishes that differential regulation of NMDA receptor subunits at the mRNA level could be a molecular basis for changes in biophysical and pharmacological properties of the NMDA receptor complex. However, even though the NMDA receptor is the best studied candidate to function as a 'plasticity switch', there are large gaps in our understanding of the complete set of factors that control the ability of synapses to rearrange during development.

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    • "[1] and reviewed in [2], [3]). Moreover, glutamate is involved in the regulation of developmental events in various brain regions, and in particular retino-recipient areas [4], [5]. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is of particular interest since it has been demonstrated to play a central role in the transduction of photic cues in the SCN [3], [6], and critical to normal development of visual pathways and associated with synaptogenesis and synaptic plasticity [4], [5], [7], [8]. "
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    ABSTRACT: Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to environmental changes in quality/quantity of light over the circadian day and annual cycle.
    PLoS ONE 05/2012; 7(5):e37496. DOI:10.1371/journal.pone.0037496 · 3.23 Impact Factor
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    • "inues to grow throughout adult life ( Easter and Stuermer , 1984 ; Stuermer , 1984 ) . During early develop - ment , the NMDA receptor is critical for detecting correlated firing from convergent RGC input and fine - tuning top - ography ( Bear et al . , 1990 ; Feldman et al . , 1990 ; Hahm et al . , 1991 ; Hickmott and Constantine - Paton , 1993 ; Hofer et al . , 1994 ; Li et al . , 1994 ; Lin and Constantine - Paton , 1998 ; Simon et al . , 1992 ; Yen et al . , 1995 ) . The roles for NMDA receptors in reducing neurite motility , pruning RGC axonal arbors , and stabilizing synaptic contacts that have been identified during early development ( Cline and Constantine - Paton , 1990 ; Debski et al . , 19"
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    ABSTRACT: Retinotectal topography is established during development and relies on the sequential recruitment of glutamate receptors within postsynaptic tectal cells. NMDA receptors underpin plastic changes at early stages when retinal ganglion cell (RGC) terminal arbors are widespread and topography is coarse; AMPA/kainate receptors mediate fast secure neurotransmission characteristic of mature circuits once topography is refined. Here, we have examined the relative contributions of these receptors to visually evoked activity in normal adult goldfish, in which retinotectal topography is constantly adjusted to compensate for the continual neurogenesis and the addition of new RGC arbors. Furthermore, we examined animals at two stages of optic nerve regeneration. In the first, RGC arbors are widespread and receptive fields large resulting in coarse topography; in the second, RGC arbors are pruned to reduce receptive fields leading to refined topography. Antagonists were applied to the tectum during multiunit recording of postsynaptic responses. Normal goldfish have low levels of NMDA receptor-mediated activity and high levels of AMPA/kainate. When coarse topography has been restored, NMDA receptor-mediated activity is increased and that of AMPA/kainate decreased. Once topography has been refined, the balance of NMDA and AMPA/kainate receptor-mediated activity returns to normal. The data suggest that glutamatergic neurotransmission in normal adult goldfish is dual with NMDA receptors fine-tuning topography and AMPA receptors allowing stable synaptic function. Furthermore, the normal operation of both receptors allows a response to injury in which the balance can be transiently reversed to restore topography and vision.
    Experimental Neurology 11/2005; 195(2):391-9. DOI:10.1016/j.expneurol.2005.05.015 · 4.70 Impact Factor
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    • "The temporal expression pattern of NR1 mRNA in the superficial superior colliculus and cortex follows the time course of synaptogenesis so that a pronounced increase of NR1 mRNA levels occurs during the late stages of retinocollicular map refinement (Hofer and Constantine-Paton, 1994; Hofer et al., 1994). These alterations are prevented when activity is experimentally blocked (Hofer et al., 1994). We hypothesized that SCI and the loss of descending innervation from brain pathways that control motor function may change NMDA receptor subunit expression. "
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    ABSTRACT: Differential assembly of N-methyl-D-aspartate (NMDA) receptor subunits determines their functional characteristics. Using in situ hybridization, we found a selective increase of the subunits NR1 and NR2A mRNA at 24 h in ventral motor neurons (VMN) caudal to a standardized spinal cord contusion injury (SCI). Other neuronal cell populations and VMN rostral to the injury site appeared unaffected. Significant up-regulation of NR2A mRNA also was seen 1 month after SCI in thoracic and lumbar VMN. The selective effects on VMN caudal to the injury site suggest that the loss of descending innervation leads to increased NMDA receptor subunit expression in these cells after SCI, which may alter their responses to glutamate. In contrast, protein levels determined by western blot analysis show decreased levels of NR2A 1 month after SCI in whole thoracic segments of spinal cord that included the injury sites. No effects of injury were seen on subunit levels in cervical or lumbar segments. Taken together with our previous study showing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit down-regulation after injury, our data suggest that glutamate receptor composition is significantly altered after SCI. These changes need to be taken into account to properly understand the function of, and potential pharmacotherapy for, the chronically injured spinal cord.
    Journal of Neurochemistry 08/2000; 75(1):174-84. DOI:10.1046/j.1471-4159.2000.0750174.x · 4.28 Impact Factor
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