CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures
| Autor: | Zhi-Li Huang, Guang Yang, Zi-Ai Zhu, Sen-Sen Lou, Xuewen Cheng, Wei Xu, Zhi-Qi Xiong, Hong-Tao Wang, Xue Feng, Yi-Yan Li |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mossy fiber (hippocampus) Patch-Clamp Techniques Glutamic Acid Biology Protein Serine-Threonine Kinases Sudden death 03 medical and health sciences Epilepsy Glutamatergic Mice 0302 clinical medicine Prosencephalon Seizures medicine Animals GABAergic Neurons Hippocampal mossy fiber Homeodomain Proteins Mice Knockout Neurons Excitatory Postsynaptic Potentials Electroencephalography medicine.disease Electrophysiology Disease Models Animal 030104 developmental biology Neurology Dentate Gyrus Mossy Fibers Hippocampal Excitatory postsynaptic potential GABAergic Neurology (clinical) Calcium-Calmodulin-Dependent Protein Kinase Type 2 Neuroscience Epileptic Syndromes Spasms Infantile 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | EpilepsiaREFERENCES. 62(2) |
| ISSN: | 1528-1167 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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