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Loss of epilepsy-associated CDKL5 kinase alters synaptic signaling pathways throughout development

ABSTRACT: Lesions of the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are associated with a severe developmental epileptic encephalopathy called CDKL5 deficiency disorder (CDD). CDKL5 is a serine-threonine kinase that has been implicated as a regulator of synaptic functioning, and its loss results in multiple behavioral phenotypes in animal models, including hippocampus-dependent learning and memory deficits. To determine how the loss of CDKL5 alters biochemical signaling pathways at the synapse and in the hippocampus in vivo, we isolated cortical synaptosomes and whole hippocampal tissue from CDD mice for proteomic and phosphoproteomic analysis. Furthermore, CDKL5 is known to have important developmental and post-developmental roles in the brain, so we collected tissues at both early postnatal and later adolescent timepoints to elucidate how signaling pathway alterations differ across development. Our DIA-based mass spectrometry results revealed that loss of CDKL5 alters multiple synaptic and hippocampal signaling pathways, with changes predominantly reflecting altered protein phosphorylation status, not changes in protein abundance. Differently regulated proteins were enriched for multiple synaptic and neuronal signaling pathways during and after early development, with a couple of notable examples including altered phosphorylation of proteins important for the synaptic vesicle cycle and Rho GTPase signaling. Overall, our findings highlight several biochemical signaling pathways that are altered in CDD and informs future mechanistic and therapeutic studies aiming to better understand and treat CDD.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: W. Andy Tao, Zhaolan Zhou

PROVIDER: PXD053259 | JPOST Repository | Thu Jun 20 00:00:00 BST 2024

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	DDA_Library_Hippocampus_20fractions.zip	Other
	DDA_Library_Synaptosome_14fractions.zip	Other
	Hippocampus_2Week_DIA_Phosphoproteomics_16%20samples.zip	Other
	Hippocampus_2_Week_Phosphoproteome.sne	Other
	Hippocampus_6Week_DIA_Phosphoproteomics_16%20samples.zip	Other

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Project description: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-/y 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-/y rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 5 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 LTP is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y 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 brains regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

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Loss of epilepsy-associated CDKL5 kinase alters synaptic signaling pathways throughout development

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