Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.
Title | Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | de Oliveira LSimões, O'Leary HE, Nawaz S, Loureiro R, Davenport EC, Baxter P, Louros SR, Dando O, Perkins E, Peltier J, Trost M, Osterweil EK, Hardingham GE, Cousin MA, Chattarji S, Booker SA, Benke TA, Wyllie DJA, Kind PC |
Journal | Mol Autism |
Volume | 15 |
Issue | 1 |
Pagination | 28 |
Date Published | 2024 Jun 14 |
ISSN | 2040-2392 |
Keywords | Animals, CA1 Region, Hippocampal, Disease Models, Animal, Epileptic Syndromes, Excitatory Postsynaptic Potentials, Genetic Diseases, X-Linked, Hippocampus, Long-Term Potentiation, Male, Protein Serine-Threonine Kinases, Pyramidal Cells, Rats, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Spasms, Infantile, Synapses |
Abstract | 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 Cdkl5 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 and plasticity would be observed in the hippocampus of Cdkl5 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 and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca permeable AMPA receptor mediated currents are unchanged in Cdkl5 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 at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD. |
DOI | 10.1186/s13229-024-00601-9 |
Alternate Journal | Mol Autism |
PubMed ID | 38877552 |
PubMed Central ID | PMC11177379 |
Grant List | T32 MH015442 / MH / NIMH NIH HHS / United States 204954/Z/16/Z / WT_ / Wellcome Trust / United Kingdom 529085 / / Simons Foundation Autism Research Initiative / |