N-Methyl-D-Aspartate Receptors, Ketamine, and Rett Syndrome: Something Special on the Road to Treatments?

Katz, David M.; Menniti, Frank S.; Mather, Robert J.

doi:10.1016/j.biopsych.2016.03.1045

Cited by 22 publications

(11 citation statements)

References 9 publications

(20 reference statements)

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“…We show that it is possible to rescue the neuronal phenotype by blocking NMDARs in mature networks, a finding that has important clinical relevance. For example, NMDAR antagonists like ketamine and memantine have been used successfully in mouse models to treat RTT 46,47 and other NDDs 45,48 and led in some cases to improvements in small open-label trials for autism 55–57 . These studies, as well as ours, provide preclinical proof of concept that NMDAR antagonists could ameliorate neurological dysfunction and reverse at least some circuit-level defects.…”

Section: Discussionmentioning

confidence: 99%

Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

et al. 2019

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Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS.

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Section: Discussionmentioning

confidence: 99%

Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

et al. 2019

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“…Since dendrites receive electrical signals and neurotransmitters from pre-synaptic neurons, a neurotransmitter signaling defect was proposed in RTT. In support of this idea, dysfunction in dopamine (Wenk 1995), serotonin (Paterson et al 2005; Ohno et al 2016), norepinephrine (Viemari 2005; Santos et al 2010), glutamate (Chao et al 2010; Abdala et al 2016), and NMDA signaling (Katz et al 2016; Patrizi et al 2016) has been observed in Mecp2 -mutant mice. Treatments that target these pathways have shown varied effects in mice, and a few have been tested in clinical trials.…”

Section: Using Mouse Models To Develop Therapeutics For Rtt Targetingmentioning

confidence: 94%

Treating Rett syndrome: from mouse models to human therapies

Vashi

Justice

2019

Mamm Genome

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Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ). Mecp2- mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.

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“…Perhaps the best example of repurposing efforts in RTT is that of the anesthetic and N -methyl-D-aspartate receptor (NMDAR) antagonist ketamine. As is extensively discussed and referenced in [11], subanesthetic doses of ketamine improve cortical function in MeCP2 +/− and MeCP2 −/y mice and may also impact repetitive movements (paw clasping) and respiratory phenotypes. Interestingly, efficacy is observed during times when ketamine exposure is observed as well as during periods after which the drug has been cleared.…”

Section: Drug Repurposingmentioning

confidence: 99%

“…This suggests that acute effects on NMDAR function and sustained downstream signaling events may both impact RTT phenotypes. Relative to other potential treatments, ketamine is an example of a compound whose efficacy has been demonstrated in multiple laboratories, in both male and female MeCP2 -knockout mice, and in acute and chronic dosing paradigms [11]. While an early trial with IV ketamine and RTT was terminated (Clinical Trial Number: NCT02562820), a Phase II clinical trial for the use of ketamine is currently enrolling (Clinical Trial Number: NCT03633058) and optimism remains high that efficacy will be observed in RTT patients.…”

Section: Drug Repurposingmentioning

confidence: 99%