Functional impairments in the perirhinal cortex of a mouse model of CDKL5 deficiency disorder are ameliorated by a GABAB receptor antagonist

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 balance between excitation and inhibition. Interestingly, GABAergic transmission mediated by parvalbumin+ interneurons was recently found enhanced in the primary visual cortex of Cdkl5-knockout (KO) mice; this might contribute to the visual deficits characteristic of the CDKL5 disorder. Further studies are needed to clarify the relation between GABAergic abnormalities in the cerebral cortex and the functional deficits observed in these mice. Here we examined the GABAergic network in the perirhinal cortex (PRC), where we previously observed a long-term potentiation (LTP) impairment associated with a visual recognition memory deficit. We found a higher number of vesicular GABA transporter (VGAT)-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 in vitro exposure to the GABAAR antagonist picrotoxin had no positive effects on LTP in PRC slices from Cdkl5-KO mice, exposure to the selective GABABR antagonist CGP55845 increased LTP magnitude, suggesting that exaggerated GABABR-mediated inhibition might contribute to LTP impairment. Moreover, acute in vivo treatment with CGP55845 restored novel object recognition in Cdkl5-KO mice, and increased the number of PSD95+ puncta and number and maturation of dendritic spines. Present data suggest that inhibition of enhanced GABABR-mediated synaptic transmission might be an effective way to improve synaptic plasticity and cognition in CDKL5 deficiency.