- CDKL5 deficiency disorder: the potential of a GABAB receptor antagonist to rescue functional and structural impairments in the perirhinal cortex of a mouse model
- Berardi, Anna Cecilia <1992>
Subject
- BIO/09 Fisiologia
Description
- CDKL5 (cyclin dependent kinase like 5) deficiency disorder ( is a severe neurodevelopmental encephalopathy characterized by early onset epilepsy and intellectual disability.Studies in mouse models have linked CDKL5 deficiency to defects in neuronal maturation and synaptic plasticity, and disruption of the excitatory/inhibitory balance. Interestingly, increased density of both GABAergic synaptic terminals and parvalbumin inhibitory interneurons was recently observed in the primary visual cortex of Cdkl5 knockout ( mice, suggesting that excessive GABAergic transmission might contribute to the visual deficits characteristic of CDD. However, the functional relevance of cortical GABAergic circuits abnormalities in these mutant mice has not been investigated so far. Here we examined GABAergic circuits in the perirhinal cortex ( of Cdkl5 KO mice, where we previously observed imp aired long term potentiation ( associated with deficits in novel object recognition ( memory. We found a higher number of GABAergic ( immunopositive terminals in the PRC of Cdkl5 KO compared to wild type mice, suggesting that increased inhibitory transmission might contribute to LTP impairment. Interestingly, while exposure of PRC slices to the GABAA receptor antagonist picrotoxin had no positive effects on LTP in Cdkl5 KO mice, the selective GABAB receptor antagonist CGP55845 restored LTP magn itude, suggesting that exaggerated GABAB receptor mediated inhibition contributes to LTP impairment in mutants. Moreover, acute in vivo treatment with CGP55845 increased the number of PSD95 positive puncta as well as density and maturation of dendritic spi nes in PRC, and restored NOR memory in Cdkl5 KO mice. The present data show the efficacy of limiting excessive GABAB receptor mediated signaling in improving synaptic plasticity and cognition in CDD mice.
Date
- 2021-11-15
Type
- Doctoral Thesis
- PeerReviewed
Format
- application/pdf
Identifier
urn:nbn:it:unibo-28068
Berardi, Anna Cecilia (2021) CDKL5 deficiency disorder: the potential of a GABAB receptor antagonist to rescue functional and structural impairments in the perirhinal cortex of a mouse model, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie