Enhanced hippocampal LTP but typical NMDA receptor and AMPA receptor function in a novel rat model of CDKL5 deficiency disorder

Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 ( CDKL5 ) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a novel Cdkl5 KO rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5 KO rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene using Crispr-Cas9 technology. We then tested our hypothesis using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results: CA1 hippocampal LTP is increased only in juvenile rats. We show that NMDA receptor function and subunit expression are unaltered throughout development, and Ca 2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 KO rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability in Cdkl5 KO rats and supported by typical expression of pre-synaptic proteins in synaptosome preparations. Together these data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits might contribute to the altered plasticity.Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal neurons across early postnatal development. Studies involving other brains regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.