Functional and Structural Impairments in the Perirhinal Cortex of a Mouse Model of CDKL5 Deficiency Disorder Are Rescued by a TrkB Agonist.

Elisa Ren,Keqiang Ye,Elisabetta Ciani,Giorgio Medici,Stefania Trazzi,Vincenzo Roncacé,Giuseppe Galvani,Roberto Rimondini,Manuela Loi,Giorgio Aicardi,Claudia Fuchs,Laura Gennaccaro

doi:10.3389/fncel.2019.00169

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental encephalopathy caused by mutations in the CDKL5 gene and characterized by early-onset epilepsy and intellectual and motor impairments. No cure is currently available for CDD patients, as limited knowledge of the pathology has hindered the development of therapeutics. Cdkl5 knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown alterations in synaptic plasticity and dendritic pattern in the cerebral cortex and in the hippocampus, but the knowledge of the molecular substrates underlying these alterations is still limited. Here, we have examined for the first time synaptic function and plasticity, dendritic morphology, and signal transduction pathways in the perirhinal cortex (PRC) of this mouse model. Being interconnected with a wide range of cortical and subcortical structures and involved in various cognitive processes, PRC provides a very interesting framework for examining how CDKL5 mutation leads to deficits at the synapse, circuit, and behavioral level. We found that long-term potentiation (LTP) was impaired, and that the TrkB/PLCγ1 pathway could be mechanistically involved in this alteration. PRC neurons in mutant mice showed a reduction in dendritic length, dendritic branches, PSD-95-positive puncta, GluA2-AMPA receptor levels, and spine density and maturation. These functional and structural deficits were associated with impairment in visual recognition memory. Interestingly, an in vivo treatment with a TrkB agonist (the 7,8-DHF prodrug R13) to trigger the TrkB/PLCγ1 pathway rescued defective LTP, dendritic pattern, PSD-95 and GluA2-AMPA receptor levels, and restored visual recognition memory in Cdkl5 KO mice. Present findings demonstrate a critical role of TrkB signaling in the synaptic development alterations due to CDKL5 mutation, and suggest the possibility of TrkB-targeted pharmacological interventions.

Highlights

To evaluate the possibility that Cdkl5 deletion may affect longterm synaptic plasticity, we induced long-term potentiation (LTP) in layers II–III of the perirhinal cortex (PRC) using Theta burst stimulation (TBS), i.e., short trains of 100 Hz pulses delivered at theta (5 Hz) frequency
We found that the magnitude of TBSinduced LTP was significantly smaller in slices from Cdkl5 −/Y mice (Figures 2A,B)
All these defects were corrected by R13 treatment. These results indicate that activation of the TrkB/phospholipase Cγ1 (PLCγ1) pathway restores the dendritic pattern of the PRC neurons in Cdkl5 −/Y mice

Summary

Introduction

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare encephalopathy characterized by early-onset intractable epileptic seizures, severe intellectual disability, gross motor impairment, stereotypies, visual impairments and autisticlike features (Kalscheuer et al, 2003; Weaving et al, 2004; BahiBuisson et al, 2008; Bahi-Buisson and Bienvenu, 2012; Moseley et al, 2012; Paine et al, 2012; Stalpers et al, 2012; Fehr et al, 2013). Cdkl KO mice recapitulate different features of CDD, exhibiting severe impairment in learning and memory, visual and respiratory deficits, and motor stereotypies (Wang et al, 2012; Amendola et al, 2014; Fuchs et al, 2014, 2015; Mazziotti et al, 2017). Immunocytochemical studies have demonstrated alterations in synaptic connectivity, which might lead to an excitation-inhibition imbalance (Pizzo et al, 2016; Sivilia et al, 2016) Together, these observations have led to the suggestion that there is an overall reduction in the number of synaptic inputs to neurons in the CDKL5-deficient brain. Cdkl deficiency in primary hippocampal neurons leads to deranged expression of the GluA2 subunit of alpha-amino-3hydroxy-5-methyl-4-isoxazole propionic acid receptors (GluA2AMPAR), and it is probable that this prompts an alteration of synaptic functions (Tramarin et al, 2018)

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Conclusion