NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, ketamine can also produce psychotomimetic effects that limit its utility as an antidepressant, raising the question of whether the clinically tolerated NMDAR antagonist memantine possesses antidepressant properties. Despite its similar potency to ketamine as an NMDAR antagonist, clinical data suggest that memantine does not exert rapid antidepressant actions for reasons that are poorly understood. In this study, we recapitulate the ketamine and memantine clinical findings in mice, showing that ketamine, but not memantine, has antidepressant-like effects in behavioral models. Using electrophysiology in cultured hippocampal neurons, we show that ketamine and memantine effectively block NMDAR-mediated miniature excitatory postsynaptic currents in the absence of Mg 2+ . However, in physiological levels of extracellular Mg 2+ , we identified key functional differences between ketamine and memantine in their ability to block NMDAR function at rest. This differential effect of ketamine and memantine extends to intracellular signaling coupled to NMDAR at rest, in that memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2 or augment subsequent expression of BDNF, which are critical determinants of ketamine-mediated antidepressant efficacy. These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDAR-mediated neurotransmission that have impacts on downstream intracellular signaling, which we hypothesize is the trigger for rapid antidepressant responses. These data provide a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission as a critical determinant necessary to elicit rapid antidepressant responses. eEF2 | spontaneous neurotransmission

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“…3K). As previously reported, AP5 perfusion caused a significant reduction in the area and decay time of mEPSCs (18) (Fig. 3 C and D).…”

Section: Memantine Exhibits Reduced Nmdar Blockade In Physiologicalsupporting

confidence: 89%

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

Gideons

Kavalali

Monteggia

2014

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

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193

152

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“…Because ␥-secretase is involved in the processing of so many different types of proteins, to hypothesize here about a specific pathway by which ␥-secretase regulates spontaneous release is beyond the scope of this study. In recent years, important physiological functions have been identified for spontaneous excitatory neurotransmission (McKinney et al, 1999;Sharma and Vijayaraghavan, 2003;Sutton et al, 2006;Espinosa and Kavalali, 2009). The current study thus adds to the growing list of potential deleterious consequences of using ␥-secretase inhibitors to treat AD (Panza et al, 2010).…”

Section: Discussionmentioning

confidence: 85%

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Pratt¹,

Zhu²,

Watari³

et al. 2011

J. Neurosci.

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With a multitude of substrates, ␥-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of ␥-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of ␥-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support ␥-secretase activity. Treatment of WT neuronal cultures with ␥-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for ␥-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.

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“…7). In fact, NMDA receptor voltagedependent blockade by magnesium at resting potentials is not absolute (Espinosa and Kavalali, 2009) and both increased extracellular availability of glutamate as well as increased receptor levels could account for the observed gain of function. Together, these data suggest that increased contribution of NMDA receptors to synaptic transmission by treatment with a-syn HNE-oligomers does not involve alterations in NMDA receptor gating.…”

Section: A-syn Hne-oligomers Increase the Nmda Component Of Synaptic mentioning

confidence: 99%

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

et al. 2012

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Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of ␣-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus.Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposuretoa-synoligomersdrivestheincreaseofglutamatergicsynaptictransmission,preventingfurtherpotentiationbyphysiologicalstimuli.Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

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NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

Cited by 65 publications

References 40 publications

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation

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