Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory. These defects were accompanied by an increased activity of GSK3β, an important inhibitory regulator of many neuronal functions. Pharmacological inhibition of GSK3β activity was able to recover hippocampal defects and cognitive performance in juvenile Cdkl5 KO mice, suggesting that GSK3β inhibitors might be a potential therapeutic option for CDKL5 disorder. As GSK3β inhibitors have been shown to have differential medication responses in young people and adults, this study was designed to examine whether GSK3β is a possible therapeutic target both in juvenile and in adult CDKL5 patients. We found that treatment with the GSK3β inhibitor Tideglusib during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice, while treatment later on in adulthood had no positive effects. These results suggest that pharmacological interventions aimed at normalizing impaired GSK3β activity might have different age-dependent outcomes in CDKL5 disorder. This is of utmost importance in the development of therapeutic approaches in CDKL5 patients and in the design of rational clinical trials.

CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

“…Spontaneous synaptic activity is impaired in hippocampal slices of a forebrain excitatory neuron specific to Cdkl5 KO mice [Nex‐cKO; ], and excitatory synaptic transmission is reduced in mouse hippocampal cultures silenced for Cdkl5 . Altered neuronal survival, dendritic development and synaptic function may underlie the severe hippocampus‐dependent cognitive impairment that characterizes Cdkl5 KO mice .…”

“…CDKL5 forms a complex with PSD‐95 and NGL‐1 at the spine level to regulate spine morphology and maintenance , and with IQ domain‐containing GTPase‐activating protein 1 (IQGAP1) and MAP1S to regulate microtubule dynamics and stability . Although data clearly suggest that CDKL5 is important for correct neuronal maturation , the role of CDKL5 in the maintenance of neuron survival has been poorly investigated. In addition, the mechanisms by which CDKL5 supports neuronal survival remain unknown.…”

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

“…These studies include the use of NMDA receptor modulators: allopregnanolone (a neurosteroid restoring normal morphology of microtubules); tineptin (an antidepressant affecting AMPA receptors); and insulin-like growth factor IGF-1, activating AKT/mTORY serotonergic receptor agonist 5-HT7R-LP-211 [55,56]. Recently, the results of a study carried out on a CDD-loaded mouse population have been published, which demonstrated the beneficial effect of GSK3β receptor (tideglusib) inhibition on hippocampal development and hippocampus-dependent learning memory in young individuals [57]. The achievements of modern technology also allow the development of methods of protein substitution therapy, which was described by Trazzi [58]; TAT-CDKL5 fusion proteins were used, which, crossing the barrier, reach the CNS while maintaining the CDKL5 protein activity.…”

Frequently Identified Genetic Developmental and Epileptic Encephalopathy: A Review Focusing on Precision Medicine

“…These defects were accompanied by increased activity of GSK3β, an important inhibitory regulator of many neuronal functions [17]. Therefore, tideglusib was tested on Cdkl5 knockout mice and results showed that tideglusib improved hippocampal development, hippocampus-dependent behaviors, and memory performance in juvenile Cdkl5 knockout mice [24].…”