CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility

Abstract

Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.

Deep brain stimulation at the basolateral amygdala alters whole-brain connectivity and synchronization and social behaviors ofTbr1deficient mice

“…Altered local and long-range functional connectivity is one of the primary features of ASD [26][27][28][29]. Mouse models have also been shown to recapitulate the connectivity deficits displayed by human patients [27,[30][31][32][33][34][35]. TBR1 deficiency is a particularly interesting case because one of the outcomes, i.e., impairment of the anterior commissure, is shared by both mouse and human [9][10][11][12][13].…”

“…Some mouse models of ASD also present connectivity deficits [6,[9][10][11][12][13][14]. However, the detailed features of rewiring alterations under ASD conditions remain elusive.…”

“…One of the primary biological features correlated with behavioral phenotypes in ASD patients is the altered neural connections [1-4] contributing to both local and long-range functional connectivity [5-8]. Some mouse models of ASD also present connectivity deficits [6, 9-14]. However, the detailed features of rewiring alterations under ASD conditions remain elusive.…”