CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures
- 5 January 2021
- Vol. 62 (2), 517-528
- https://doi.org/10.1111/epi.16805
Abstract
Objective Mutations of the cyclin‐dependent kinase‐like 5 (CDKL5) gene cause severe neurodevelopmental disorders characterized by intractable epilepsy, intellectual disability, and autism. Multiple mouse models generated for mechanistic studies have exhibited phenotypes similar to some human pathological features, but none of the models has developed one of the major symptoms affecting CDKL5 deficiency disorder (CDD) patients: intractable recurrent seizures. As disrupted neuronal excitation/inhibition balance is closely associated with the activity of glutamatergic and γ‐aminobutyric acidergic (GABAergic) neurons, our aim was to study the effect of the loss of CDKL5 in different types of neurons on epilepsy. Methods Using the Cre‐LoxP system, we generated conditional knockout (cKO) mouse lines allowing CDKL5 deficiency in glutamatergic or GABAergic neurons. We employed noninvasive video recording and in vivo electrophysiological approaches to study seizure activity in these Cdkl5 cKO mice. Furthermore, we conducted Timm staining to confirm a morphological alteration, mossy fiber sprouting, which occurs with limbic epilepsy in both human and mouse brains. Finally, we performed whole‐cell patch clamp in dentate granule cells to investigate cell‐intrinsic properties and synaptic excitatory activity. Results We demonstrate that Emx1‐ or CamK2α‐derived Cdkl5 cKO mice manifest high‐frequency spontaneous seizure activities recapitulating the epilepsy of CDD patients, which ultimately led to sudden death in mice. However, Cdkl5 deficiency in GABAergic neurons does not generate such seizures. The seizures were accompanied by typical epileptic features including higher amplitude spikes for epileptiform discharges and abnormal hippocampal mossy fiber sprouting. We also found an increase in spontaneous and miniature excitatory postsynaptic current frequencies but no change in amplitudes in the dentate granule cells of Emx1‐cKO mice, indicating enhanced excitatory synaptic activity. Significance Our study demonstrates that Cdkl5 cKO mice, serving as an animal model to study recurrent spontaneous seizures, have potential value for the pathological study of CDD‐related seizures and for therapeutic innovation.Keywords
Funding Information
- Chinese Academy of Sciences (QYZDJ‐SSW‐SMC010)
- Science and Technology Commission of Shanghai Municipality (18JC1410100)
This publication has 35 references indexed in Scilit:
- Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in miceProceedings of the National Academy of Sciences of the United States of America, 2012
- Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC NeuronsNeuron, 2011
- CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 SignalingJournal of Neuroscience, 2010
- CDKL5 Expression Is Modulated during Neuronal Development and Its Subcellular Distribution Is Tightly Regulated by the C-terminal TailJournal of Biological Chemistry, 2008
- Key clinical features to identify girls with CDKL5 mutationsBrain, 2008
- Maternal origin of a novel C‐terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndromeClinical Genetics, 2006
- CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disordersHuman Molecular Genetics, 2005
- Kindling and status epilepticus models of epilepsy: rewiring the brainProgress in Neurobiology, 2004
- A CamKIIα iCre BAC allows brain‐specific gene inactivationgenesis, 2001
- Identification and Characterization of a Novel Serine– Threonine Kinase Gene from the Xp22 RegionGenomics, 1998