Enhanced NMDA receptor-dependent LTP in the epileptic CA1 area via upregulation of NR2B

Müller, Luisa; Tokay, Tursonjan; Porath, Katrin; Köhling, Rüdiger; Kirschstein, Timo

doi:10.1016/j.nbd.2012.12.011

Cited by 62 publications

(57 citation statements)

References 59 publications

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“…This is in contrast to previous mGlu 5 PAMs, which induce robust potentiation of TBS-LTP (Ayala et al, 2009; Noetzel et al, 2013). Induction of LTP at this synapse is known to be NMDAR-dependent (Ben-Ari et al, 1992; Harris et al, 1984; Muller et al, 2013). Thus, this finding, together with the lack of ability of VU0409551 to potentiate mGlu 5 modulation of NMDAR currents, is consistent with the hypothesis that mGlu 5 -induced potentiation of hippocampal LTP is dependent on the ability of mGlu 5 to potentiate NMDAR currents (Ben-Ari et al, 1992; Collingridge et al, 2013; Mannaioni et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Biased mGlu 5 -Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu 5 Modulation of NMDAR Currents

Rook

Xiang

et al. 2015

Neuron

117

201

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Summary Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq–mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy.

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Section: Discussionmentioning

confidence: 99%

Biased mGlu 5 -Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu 5 Modulation of NMDAR Currents

Rook

Xiang

et al. 2015

Neuron

117

201

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“…The lower threshold might develop because the aberrant GCs have intrinsic properties that lead to increased excitability (Althaus et al, 2014), or have a greater ratio of excitatory afferent input relative to inhibitory input (Zhan et al, 2010) like the dominant GCs in Figure 6B. In addition, the synapses onto CA3 pyramidal cells may undergo LTP more readily in the epileptic brain because the threshold for synaptic plasticity is lower, in general, in animal models of epilepsy (Lopantsev et al, 2009; Muller et al, 2013). The outcome would be an easily activated pathway for seizures to propagate through hippocampus.…”

Section: Dominant Gcs Mossy Fiber Variance and Their Implicationsmentioning

confidence: 99%

Corruption of the dentate gyrus by “dominant” granule cells: Implications for dentate gyrus function in health and disease

Scharfman

Myers

2016

Neurobiology of Learning and Memory

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The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell ‘backprojections’ play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance – ‘mossy fiber variance’ – which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become ‘dominant,’ one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of ‘dominant’ GCs – subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network.

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“…For instance, recurrent seizures reduce hippocampal LTP and function in rats (Zhou et al, 2007;Chen et al, 2013) whereas febrile seizures in early life enhance hippocampal LTP and decrease LTD) (Notenboom et al, 2010). Additionally, sustained Status Epilepticus (SE) induced by pilocarpine enhances LTP in hippocampal CA1 neurons of rats (Mu¨ller et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of long-term potentiation in the schaffer-CA1 pathway by repetitive high-intensity sound stimulation

et al. 2015

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Enhanced NMDA receptor-dependent LTP in the epileptic CA1 area via upregulation of NR2B

Cited by 62 publications

References 59 publications

Biased mGlu 5 -Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu 5 Modulation of NMDAR Currents

Biased mGlu 5 -Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu 5 Modulation of NMDAR Currents

Corruption of the dentate gyrus by “dominant” granule cells: Implications for dentate gyrus function in health and disease

Inhibition of long-term potentiation in the schaffer-CA1 pathway by repetitive high-intensity sound stimulation

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