Spike timing–dependent long-term depression requires presynaptic NMDA receptors

Rodríguez‐Moreno, Antonio; Paulsen, Ole

doi:10.1038/nn.2125

Cited by 142 publications

(234 citation statements)

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“…The t-LTD is a neural substrate of some forms of learning and memory that depends on the precise timing of a presynaptic input and a postsynaptic action potential (28). t-LTD occurs when a postsynaptic spike is followed by a presynaptic spike and reflects presynaptic changes in neurotransmitter release that specifically rely on activation of presynaptic NMDA receptors (43). To explore the impact of 5-HT 2A receptor stimulation upon t-LTD induction at thalamocortical synapses, we used a protocol consisting of 75 pairings of an action potential at a layer V pyramidal neuron preceding a layer I-generated EPSP.…”

Section: Resultsmentioning

confidence: 99%

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre

Berthoux

Bundel

et al. 2016

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

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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: Resultsmentioning

confidence: 99%

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Barre

Berthoux

Bundel

et al. 2016

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

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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%

“…PreNMDARs are therefore likely to bias plasticity and circuit modifica-tion. In early neocortical development, preNMDARs mediate timing-dependent LTD (tLTD) at L4 to L2/3 synapses [48,66], but tLTD at horizontal L2/3 to L2/3 synapses requires postsynaptic NMDARs [67 •• ,68]. These mechanistic differences may underlie the considerably longer tLTD window at L4 to L2/3 synapses [67 •• ] (Figure 3a-c).…”

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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“…Plasticity of synapses between excitatory neurons of layer 4 and layer 2/3 in the barrel cortex has been studied for years as a model of spike timing-dependent plasticity, in which the temporal relation between pre-and post-synaptic action potentials controls synaptic plasticity [48][49][50]. Spike timing-dependent long-term depression (t-LTD) was known to require activation of both CB1Rs and pre-synaptic NMDARs, but how both receptor types cooperatively lead to t-LTD was unknown [48,[51][52][53]. A recent study by Thomas Nevian's laboratory has revealed that astrocytes are crucially involved in this form of synaptic plasticity [11].…”

Section: Role Of Astrocytes In the Regulation Of Long-term Synaptic Pmentioning

confidence: 99%

Astrocytes in endocannabinoid signalling

Navarrete

Díez

Araque

2014

Phil. Trans. R. Soc. B

112

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Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour.

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Spike timing–dependent long-term depression requires presynaptic NMDA receptors

Cited by 142 publications

References 15 publications

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

Synapse-type-specific plasticity in local circuits

Astrocytes in endocannabinoid signalling

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