Homeostatic plasticity and NMDA receptor trafficking

Pérez‐Otaño, Isabel; Ehlers, Michael

doi:10.1016/j.tins.2005.03.004

Cited by 319 publications

(236 citation statements)

References 115 publications

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“…Furthermore, specific AMPAr and NMDAr conductances are not affected by changes in putative synaptic weight which, although in line with many theoretical studies of plasticity induction, is clearly at odds with the situation in vivo [18,[42][43][44][45][46][47][48]. It has been demonstrated that changes in AMPAr conductance associated with the expression of long-term synaptic plasticity are accompanied by concomitant changes in NMDAr conductance [69,76]. This has interesting implications for further synaptic plasticity -as both the level of depolarisation in the spine and the level of NMDAr-dependent Calcium influx generated by that depolarisation will be concurrently modulated, possibly contributing to the 'lock-in' of changes in synaptic conductance observed experimentally [37].…”

Section: Discussionsupporting

confidence: 72%

“…This prediction could be tested through experimental measurements of the NMDAr-[Ca 2+ ] current generated by spike and triplet pairing protocols at different stimulation frequencies. It is well known that the activity-dependent NR2A / NR2B subunit composition of NMDAr has a significant influence on the properties and temporal profile of synaptic currents, particularly at the high and low firing rates associated with LTP and LTD induction [68,69]. Measuring the changes in synaptic strength generated by spike and triplet pairing protocols under regimes of selective pharmacological blockade would also allow the dynamics of kinase and phosphotase activity to be more precisely delineated, providing further data to constrain the corresponding kinetic models.…”

Section: Discussionmentioning

confidence: 99%

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Calcium control of triphasic hippocampal STDP

Bush¹,

Jin

2012

J Comput Neurosci

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Synaptic plasticity is believed to represent the neural correlate of mammalian learning and memory function. It has been demonstrated that changes in synaptic conductance can be induced by approximately synchronous pairings of pre-and post-synaptic action potentials delivered at low frequencies. It has also been established that NMDAr-dependent Calcium influx into dendritic spines represents the critical signal for plasticity induction, and can account for this spike-timing dependent plasticity (STDP) as well as experimental data obtained using other stimulation protocols. However, subsequent empirical studies have delineated a more complex relationship between spike-timing, firing rate, stimulus duration and post-synaptic bursting in dictating changes in the conductance of hippocampal excitatory synapses. It has yet to be established whether the Calcium control hypothesis can account for this more recent data. Here, we present a detailed biophysical model of single dendritic spines on a CA1 pyramidal neuron, describe the NMDAr-dependent Calcium influx generated by different stimulation protocols, and present a parsimonious model of Calcium driven kinase and phosphotase dynamics that dictate transitions between binary synaptic weight states. We demonstrate the manner in which this model can account for various experimental observations of synaptic plasticity and be used to make predictions regarding the dynamics of depolarisation and NMDAr activation generated by STDP protocols as well as the synaptic weight change induced under other experimental conditions. We then discuss how this parsimonious, unified computational model of synaptic plasticity might be utilised to appraise the activity-dependent refinement of neural circuitry induced by more realistic firing patterns. IntroductionSynaptic plasticity -the process of activity dependent change in synaptic conductance -is widely believed to represent the neural correlate of mammalian learning and memory function [1][2][3]. Since the first experimental demonstrations of long-term potentiation (LTP) and depression (LTD), a wealth of empirical data regarding the induction, expression and maintenance of synaptic plasticity in different cortical regions has been obtained [4][5][6][7][8]. In spite of the heterogeneity of plasticity mechanisms observed throughout the brain, changes in the strength of excitatory synapses afferent on CA1 pyramidal neurons in the hippocampus represent the best studied form in the mammalian cortex [9][10][11][12]. At these synapses, Calcium influx into dendritic spines represents the critical signal for synaptic plasticity induction [13][14][15][16][17][18][19][20]. Large, transient elevations in intracellular [Ca 2+ ] generate LTP via the preferential activation of kinase pathways while modest, sustained elevations in intracellular [Ca 2+ ] generate LTD via the preferential activation of phosphotase pathways [21][22][23][24][25]. Initially, empirical observations of synaptic plasticity were mediated by tetanic stimulation protoc...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Calcium control of triphasic hippocampal STDP

Bush¹,

Jin

2012

J Comput Neurosci

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“…However, a number of studies have challenged this notion by demonstrating the activitydependent regulation of synaptic NMDA receptor number (Wenthold, et al, 2003). This occurs via regulation of NMDA receptor trafficking, a generic term for movement between different cellular domains such as the ER, golgi, endosomes, and various microdomains on the cell surface including the synapse (Perez-Otano and Ehlers, 2005). Homeostatic enhancement of NMDA receptor clustering at the synapse has also been observed following chronic inhibition of synaptic activity or direct inhibition of NMDA receptors (Rao and Craig, 1997).…”

Section: Nmda Receptor Trafficking and Synaptic Targetingmentioning

confidence: 99%

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

Carpenter-Hyland

Chandler

2007

Pharmacology Biochemistry and Behavior

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It is now known that brain development continues into adolescence and early adulthood and is highly influenced by experience-dependent adaptive plasticity during this time. Behaviorally, this period is also characterized by increased novelty-seeking and risk-taking. This heightened plasticity appears to be important in shaping behaviors and cognitive processes that contribute to proper development of an adult phenotype. However, increasing evidence has linked these same experience-dependent learning mechanisms with processes that underlie drug addiction. As such, the adolescent brain appears be particularly susceptible to experience-dependent learning processes associated with consumption of alcohol and addictive drugs. At the level of the synapse, homeostatic changes during ethanol consumption are invoked to counter the destabilizing effects of ethanol on neural networks. This homeostatic response may be especially pronounced in the adolescent and young adult brain due to its heightened capacity to undergo experience-dependent changes, and appears to involve increased synaptic targeting of NMDA receptors. Interestingly, recent work from our lab also indicates that the enhanced synaptic localization of NMDA receptors promotes increases in the size of dendritic spines. This increase may represent a structural-based mechanism that supports the formation and stabilization of maladapted synaptic connections that, in a sense, "fix" the addictive behavior in the adolescent and young adult brain.

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“…[20][21][22][23] These interactions are involved in receptor clustering at the synaptic membrane, downstream signaling including modulation of kinase and phosphatase activity, as well as regulated synaptic trafficking of the NMDA receptor. [24][25][26][27][28][29][30] In addition, binding of newly synthesized NMDA receptor subunits to PSD-95 or SAP102 links the receptor to different intracellular trafficking pathways, which is essential for its trafficking from the ER/Golgi complex to the PSD. [31][32][33][34] Changes in the expression of transcripts encoding NMDA receptor subunits in the prefrontal cortex have previously been described in post-mortem schizophrenic brains.…”

Section: Introductionmentioning

confidence: 99%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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Homeostatic plasticity and NMDA receptor trafficking

Cited by 319 publications

References 115 publications

Calcium control of triphasic hippocampal STDP

Calcium control of triphasic hippocampal STDP

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

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