Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

Corlew, Rebekah; Brasier, Daniel J.; Feldman, Daniel E.; Philpot, Benjamin D.

doi:10.1177/1073858408322675

Cited by 155 publications

(175 citation statements)

References 112 publications

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“…Moreover, blockade of DOI-elicited potentiation of NMDA currents by ifenprodil showed involvement of GluN2B-containing NMDA receptors. Although NMDA receptors were classically considered as postsynaptic receptors, increasing evidence indicates that they are also expressed presynaptically, and that up-regulation of presynaptic NMDA receptors enhances the probability of spontaneous and evoked neurotransmitter release at cortical, hippocampal, and cerebellar synapses (53). Moreover, the GluN2B subunit has been identified as one of the subunits of cortical presynaptic NMDA receptors (53), an observation confirmed in the present study.…”

Section: Discussionsupporting

confidence: 83%

“…Although NMDA receptors were classically considered as postsynaptic receptors, increasing evidence indicates that they are also expressed presynaptically, and that up-regulation of presynaptic NMDA receptors enhances the probability of spontaneous and evoked neurotransmitter release at cortical, hippocampal, and cerebellar synapses (53). Moreover, the GluN2B subunit has been identified as one of the subunits of cortical presynaptic NMDA receptors (53), an observation confirmed in the present study. Collectively, these findings strongly support a mechanism whereby the activation of presynaptic 5-HT 2A receptors expressed on thalamocortical afferents might locally induce, via PKC, the phosphorylation of presynaptic GluN2B-containing NMDA receptors.…”

Section: Discussionsupporting

confidence: 83%

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Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre

Berthoux

Bundel

et al. 2016

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

113

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Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT) 2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT 2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT 2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT 2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT 2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.T he prefrontal cortex (PFC) is a brain region critical for many high-level cognitive processes, such as executive functions, attention, and working and contextual memories (1). Pyramidal neurons located in layer V of the PFC integrate excitatory glutamatergic inputs originating from both cortical and subcortical areas. The latter include the mediodorsal thalamus (MD) nuclei, which project densely to the medial PFC (mPFC) and are part of the neuronal network underlying executive control and working memory (2-4). Disruption of this network has been involved in cognitive symptoms of psychiatric disorders, such as schizophrenia (3, 5). These symptoms severely compromise the quality of life of patients and remain poorly controlled by currently available antipsychotics (3, 6).The PFC is densely innervated by serotonin (5-hydroxytryptamine, 5-HT) neurons originating from the dorsal and median raphe nuclei and numerous lines of evidence indicate a critical role of 5-HT in the control of emotional and cognitive functions depending on PFC activity (7,8). The modulatory action of 5-HT reflects its complex pattern of effects on cortical network activity, depending on the 5-HT receptor subtypes involved, and on receptor localization in pyramidal neurons, GABAergic interneurons or nerve terminals of afferent neurons.Among the 14 5-HT receptor subtypes, the 5-HT 2A receptor is a Gq protein-coupled receptor (9, 10) particularly enriched in the mPFC, with a predominant expression in apical dendrites of layer V pyramidal neurons (11)(12)(13)(14). Moreover, a low proportion of 5-HT 2A receptors was detected presynaptically on thalamocortical fibers (12,(15)(16)(17).Activation of 5-HT 2A receptors exerts complex effects upon the activity of the PFC network (18). The most prominent one is an increase in p...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 83%

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre

Berthoux

Bundel

et al. 2016

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

113

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“…Because our studies also reveal enhancement in presynaptic NMDAR-mediated glutamate release in these enlarged boutons, the potential consequences of α7 blockade may include a variety of downstream events, such as alteration of postsynaptic transmission and synaptic strength (16). Immunocytochemical studies revealed the presence of NR1, NR2 and GluR1 subunits in the enlarged glutamatergic presynaptic boutons.…”

Section: Discussionmentioning

confidence: 59%

“…Presynaptic NMDARs have recently been implicated in cortical synaptic function and plasticity (16). They exist at higher levels early in development, and are involved in regulation of transmitter release and forms of LTD (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

Lin

Vicini

Hsu

et al. 2010

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

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In association with NMDA receptors (NMDARs), neuronal α7 nicotinic ACh receptors (nAChRs) have been implicated in neuronal plasticity as well as neurodevelopmental, neurological, and psychiatric disorders. However, the role of presynaptic NMDARs and their interaction with α7 nAChRs in these physiological and pathophysiological events remains unknown. Here we report that axonal α7 nAChRs modulate presynaptic NMDAR expression and structural plasticity of glutamatergic presynaptic boutons during early synaptic development. Chronic inactivation of α7 nAChRs markedly increased cell surface NMDAR expression as well as the number and size of glutamatergic axonal varicosities in cortical cultures. These boutons contained presynaptic NMDARs and α7 nAChRs, and recordings from outside-out pulled patches of enlarged presynaptic boutons identified functional NMDAR-mediated currents. Multiphoton imaging of presynaptic NMDAR-mediated calcium transients demonstrated significantly larger responses in these enlarged boutons, suggesting enhanced presynaptic NMDAR function that could lead to increased glutamate release. Moreover, whole-cell patch clamp showed a significant increase in synaptic charge mediated by NMDAR miniature EPSCs but no alteration in the frequency of AMPAR miniature EPSCs, suggesting the selective enhancement of postsynaptically silent synapses upon inactivation of α7 nAChRs. Taken together, these findings indicate that axonal α7 nAChRs modulate presynaptic NMDAR expression and presynaptic and postsynaptic maturation of glutamatergic synapses, and implicate presynaptic α7 nAChR/NMDAR interactions in synaptic development and plasticity. silent synapse | synaptic development | synaptic plasticity | alpha bungarotoxin | cytisine

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“…PreNMDARs also mediate diverse forms of LTP and LTD at subsets of synapses, including timing-dependent LTD at cortical synapses and theta-burst stimulation induced corticalstriatal LTP [45,[64][65][66]. PreNMDARs are therefore likely to bias plasticity and circuit modifica-tion.…”

Section: Synapse-type-specific Long-term Plasticitymentioning

confidence: 99%

Synapse-type-specific plasticity in local circuits

Larsen

Sjöström

2015

Current Opinion in Neurobiology

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Neuroscientists spent decades debating whether synaptic plasticity was presynaptically or postsynaptically expressed. It was eventually concluded that plasticity depends on many factors, including cell type. More recently, it has become increasingly clear that plasticity is regulated at an even finer grained level; it is specific to the synapse type, a concept we denote synapse-typespecific plasticity (STSP). Here, we review recent developments in the field of STSP, discussing both long-term and short-term variants and with particular emphasis on neocortical function. As there are dozens of neocortical cell types, there is a multiplicity of forms of STSP, the vast majority of which have never been explored. We argue that to understand the brain and synaptic diseases, we have to grapple with STSP.

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Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

Cited by 155 publications

References 112 publications

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

Synapse-type-specific plasticity in local circuits

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