Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder

Abstract

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.

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

“…Of note, work in mouse models of NDDs show that the changes in NMDARs expression are temporally and spatially restricted. This illustrates the importance of evaluating at what developmental age and in which brain regions changes in NMDAR expression occur, which is especially relevant for the design of rescue strategies 44–48 . Our data shows that NR1 is upregulated in KS iNeurons of cortical identity and support the idea that dysfunctional glutamatergic neurotransmission plays a role in NDDs.…”

“…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.…”

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

“…Studies have been conducted to develop precise therapy based on the biological, metabolic and genetic basis of CDD. These studies include the use of NMDA (N-methyl-D-aspartate) receptor modulators [50]; allopregnanolone (a neurosteroid that restores normal microtubule morphology) [51,52]; tianeptine, which is an antidepressant affecting AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [53]; or insulin-like growth factor IGF-1 activating the Akt/mTOR pathway [54]. Hopes are related to gene therapy as a causal treatment for disorders due to CDKL5 mutations.…”

Kinase Signaling in Dendritic Development and Disease

“…CDKL5 knockout mouse exhibit dendritic hypotrophy in granule cells of the hippocampus (Fuchs et al, 2014). Enhanced NMDAR signaling and circuit hyperexcitability were shown to underlie autistic-like features in mouse models of CDKL5 Syndrome (Tang et al, 2019). Recently, direct target substrates of CDKL5 in the brain were identified, which included microtubule regulators Microtubule Associated Protein 1S (MAP1S), Microtubule End Binding Protein 2 (EB2) and RhoGTPase activator ARHGEF2 (Baltussen et al, 2018).…”