Activity‐dependent tuning and the NMDA receptor

Debski, Elizabeth A.; Cline, Hollis T.; Constantine‐Paton, Martha

doi:10.1002/neu.480210103

Cited by 73 publications

(23 citation statements)

References 67 publications

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“…9), suggesting that, in addition to its GLY-like properties, HCY is a low-affinity agonist at the glutamate site (Lipton et al 1997). This may be critical if HCY is elevated during pregnancy or childhood, considering that low chronic NMDAR activation that is not correlated with presynaptic input causes functional depression and synapse elimination in the developing brain (Colonnese et al 2006;Debski et al 1990). We also show in Fig.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

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Section: Discussionmentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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“…Thus, we propose the following model for the mechanism of expression of NMDA receptor-dependent STP and LTP of AMPA receptor-mediated synaptic responses. NMDA receptor activation is known to be critical for glutamatergic synapse stabilization during development (26), and thus, we assume that a close alignment of NMDA receptors and presynaptic release sites emerges from the process of synapse formation. For synapses in the unpotentiated state, we further assume that AMPA receptors have a wider spatial distribution, with many beyond the range of effective concentration of released neurotransmitter.…”

Section: Discussionmentioning

confidence: 99%

Novel expression mechanism for synaptic potentiation: Alignment of presynaptic release site and postsynaptic receptor

Xie

Liaw

Baudry

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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A combination of experimental and modeling approaches was used to study cellular-molecular mechanisms underlying the expression of short-term potentiation (STP) and long-term potentiation (LTP) of glutamatergic synaptic transmission in the hippocampal slice. Electrophysiological recordings from dentate granule cells revealed that highfrequency stimulation of perforant path afferents induced a robust STP and LTP of both (؎)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-Daspartic acid (NMDA) receptor-mediated synaptic responses. However, the decay time constant for STP of the AMPA receptor-mediated excitatory postsynaptic potential was approximately 6 min, whereas the decay time constant for STP of the NMDA receptor-mediated excitatory postsynaptic potential was only 1 min. In addition, focal application of agonists during the expression of STP revealed that the magnitude of conductance change elicited by NMDA application was significantly enhanced, whereas the magnitude of conductance change elicited by application of AMPA remained constant. These findings are most consistent with a postsynaptic mechanism of STP and LTP. Different putative mechanisms were evaluated formally using a computational model that included diffusion of glutamate within the synaptic cleft, different kinetic properties of AMPA and NMDA receptor͞channels, and geometric relations between presynaptic release sites and postsynaptic receptor͞channels. Simulation results revealed that the only hypothesis consistent with experimental data is that STP and LTP ref lect a relocation of AMPA receptor͞channels in the postsynaptic membrane such that they become more closely ''aligned'' with presynaptic release sites. The same mechanism cannot account for STP or LTP of NMDA receptor-mediated responses; instead, potentiation of the NMDA receptor subtype is most consistent with an increase in receptor sensitivity or number.Long-term potentiation (LTP) is a widely studied form of use-dependent synaptic plasticity expressed robustly by glutamatergic synapses of the hippocampus. The initial stage of LTP expression, typically identified as short-term potentiation (STP), is characterized by a rapid decay in the magnitude of potentiation to an asymptotic, steady-state level. Although there is a convergence of evidence concerning the cellular͞ molecular mechanisms mediating the induction of N-methyl-D-aspartic acid (NMDA) receptor-dependent STP and LTP (1), there remains substantial debate as to whether the expression of potentiation reflects change in presynaptic release mechanisms or postsynaptic receptor-channel function. Because of the synaptic coexistence of (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and NMDA glutamatergic receptor subtypes (2), substantial differences in the magnitude of LTP expressed by AMPA and NMDA receptors would favor a mechanism that is postsynaptic in origin. Several studies have reported a more substantial induction of AMPA receptor-mediated LTP compared with NMDA receptormedi...

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“…In fish and frog, terminal arbors of regenerating optic axons are initially diffuse, as in some developing systems (Nakamura and O' Leary, 1989;Simon and O'Leary, 1990). Projections are thought to be sharpened subsequently by correlated patterns of electrical activity between neighbouring ganglion cells (Debski et al, 1990;Schmidt, 1993). Such fibre/fibre interactions may be absent or abnormal during optic nerve regeneration in lizards and, as a result, terminals of regenerating optic axons would not refine.…”

Section: Axonal Navigation and Map Formationmentioning

confidence: 95%

Optic nerve regenerates but does not restore topographic projections in the lizardCtenophorus ornatus

et al. 1997

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In adult fish and amphibians, the severed optic nerve regenerates and visual behaviour is restored. By contrast, optic axons do not regenerate in the more recently evolved birds and mammals. Here we have investigated optic nerve regeneration in a member of the class Reptilia, phylogenetically intermediate between the fish and amphibians and the birds and mammals. We assessed visual recovery anatomically and behaviourally one year after unilateral optic nerve crush in the adult ornate dragon lizard. Ctenophorus ornatus. Ganglion cell densities and numbers of axons in the optic nerve on either side of the crush site indicated that two-thirds of ganglion cells survived axotomy and regrew their axons. However, myelination fell from a mean of 21% in normals to 5.5% and 3%, proximal and distal to the crush, respectively. Anterograde labelling of the entire optic nerve showed that axons regenerated along essentially normal pathways and that the major projection, as in normals, was to the superficial one-third of the contralateral optic tectum. However, localised retinal injections indicated that regenerated projections lacked retinotopic order. Any one retinal region projected to the entire tectum. This feature presumably explains why the experimental lizards consistently appeared blind to stimuli via the regenerated nerve. Our findings indicate that although axons regenerate along essentially normal pathways in adult lizards, conditions within the visual centres do not allow regenerating optic axons to select appropriate central connections. In a wider context, the result suggests that the ability for regenerating central axons to form topographic maps may also have been lost in the more recently evolved vertebrate classes.

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Activity‐dependent tuning and the NMDA receptor

Cited by 73 publications

References 67 publications

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Novel expression mechanism for synaptic potentiation: Alignment of presynaptic release site and postsynaptic receptor

Optic nerve regenerates but does not restore topographic projections in the lizardCtenophorus ornatus

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