Individuals with X-linked CDKL5 deficiency disorder (CDD) exhibit many features common to autism spectrum disorder (ASD), including increased risk of seizures, cognitive impairment and altered sensory sensitivity. Cdkl5 deletion in rodent models recapitulates several of these features, disrupts arousal and may dysregulate cholinergic signaling^{^1,2}. Recent work in rodents suggests that Cdkl5 deletion may also be associated with hyperconnectivity across cortical areas³. Altered functional connectivity might explain several phenotypic observations in individuals with CDD, including seizure prevalence and cognitive disruption.

Jessica Cardin and Michael Higley have recently shown that behavioral state is robustly linked to dynamic fluctuations in long-range functional connectivity in cortical networks. Their preliminary imaging in Cdkl5-deficient mice suggests that mutants exhibit globally enhanced ipsilateral cortical functional connectivity regardless of behavioral state, but selectively enhanced interhemispheric connectivity between frontal cortical areas. Their previous work found that time-varying cholinergic (ACh) modulation was coupled to state-dependent patterning of cortical network activity and selectively regulated activity levels in frontal cortical areas in wild-type mice⁴. In contrast, noradrenergic (NE) signaling may regulate long-range functional connectivity between cortical areas, based on ongoing work from the Cardin lab.

These findings suggest a potential role for neuromodulatory dysregulation in the altered functional connectivity observed in Cdkl5-deficient animals. However, little is known about the impact of Cdkl5 deficiency on neuromodulatory signaling. Furthermore, the relationship between altered local and long-range synaptic dynamics, neuromodulatory regulation and disrupted functional connectivity in mutants remains unclear. Cardin and Higley therefore plan to use mesoscopic imaging in freely moving and head-fixed animals to measure calcium and neuromodulatory signals and to assess functional connectivity across the dorsal neocortex in Cdkl5-deficient animals and littermate controls. They will further use ex vivo synaptic physiology and optogenetics to examine the impact of Cdkl5 deficiency on local and long-range synaptic dynamics and sensitivity to neuromodulatory signals.

Cardin and Higley will test the hypotheses that (1) Cdkl5 deletion broadly disrupts long-range functional connectivity in the mouse cortex and (2) this dysfunction follows from alterations in glutamatergic synaptic strength and sensitivity to neuromodulation. Their long-term goal is to understand the impact of Cdkl5 deficiency on the spatiotemporal dynamics of neuromodulatory signaling in the cortex and on regulation of cortical functional connectivity. The team expects their results will generate new insights into the role of disrupted neuromodulation in CDD and fill a critical gap in our understanding of the impact of neurodevelopmental dysregulation of long-range functional connectivity.

1. Artoni P. et al. Proc. Natl. Acad. Sci. U. S. A. 117, 23298–23303 (2020) PubMed
2. Adhikari A. et al. Hum. Mol. Genet. 31, 3032–3050 (2022) PubMed
3. Awad P.N. et al. Mol. Psychiatry 29, 1698–1709 (2024) PubMed
4. Lonani S. et al. Nat. Neurosci. 25, 1706–1713 (2022) PubMed