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.
Highlights
cyclin-dependent kinase-like 5 (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
Our previous findings showed that CDKL5 deficiency disorder (CDD)-related learning and memory impairment has origins in forebrain glutamatergic neurons in mice[14]
Given that CDKL5 is highly expressed in forebrain GABAergic neurons, we generated conditional knockout mice selectively lacking CDKL5 in this cell population (DlxcKO) using the Dlx-5/6 Cre driver[17] (Supplemental Fig. 1A, B)
Summary
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. Selectively ablating CDKL5 from glutamatergic neurons leads to increased glutamatergic and GABAergic synaptic transmission, disrupted microcircuit dynamics, and learning and memory impairment[14] While some of these differences are potentially attributable to different genetic backgrounds of mouse models of CDD, the differences between Cdkl[5] constitutive knockout mice and Nex-cKO mice suggest the existence of additional, non-glutamatergic mechanisms that may mediate CDD-related behavioral deficits. We selectively ablate CDKL5 expression in forebrain GABAergic neurons (Dlx-cKO) We found that these mice exhibit an autistic-like phenotype, but, in contrast to Nex-cKO mice, show preserved learning and memory[14]. Our findings support a novel mechanism by which CDKL5 loss in GABAergic neurons leads to excessive NMDAR signaling and contribute to the etiology of autistic-like behaviors in mouse models of CDD
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