Special Seminar with Dr. Jacque Pak Kan Ip: Functional and Molecular Dissection of Cortical Visual Impairment in CDKL5 Deficiency Disorder

Date: Friday, November 1, 2024
Location: Simons Center Conference room, 46-6011 + Zoom [https://mit.zoom.us/j/99250543803]

Speaker: Jacque Pak Kan Ip, Ph.D.

Affiliation: School of Biomedical Sciences, Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong

Host: Dr. Mriganka Sur

Talk title: Functional and Molecular Dissection of Cortical Visual Impairment in CDKL5 Deficiency Disorder

Abstract: CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder linked to the X chromosome and caused by genetic deficits in Cyclin Dependent Kinase-like 5 (CDKL5). Initially categorized as the early-onset-seizure variant of Rett syndrome, CDD is now recognized as a distinct condition with its own ICD-10 code (G40.42) assigned by the World Health Organization. However, CDD remains relatively understudied compared to other X-linked neurodevelopmental disorders such as Rett syndrome and Fragile X syndrome. Individuals with CDD experience a range of symptoms, including global developmental delay, motor dysfunction, early-onset epilepsy, learning disabilities, and autistic features. Notably, cortical visual impairment is a common clinical feature observed in at least 75% of CDD patients. Although cortical visual impairment has been suggested as a potential functional biomarker, the developmental and specific mechanisms underlying sensory processing impairments caused by CDKL5 deficits are not well understood. CDKL5 is a serine/threonine kinase, and several substrates have been identified. While research has provided insights into its molecular and cellular functions of CDKL5, its direct connection to the microcircuit development and cortical visual impairment seen in CDD is yet to be established. To address this, our study utilizes a CDD mouse model and employs in vivo two-photon calcium imaging to investigate how CDKL5 deficiency in the primary visual cortex (V1) contribute to developmental and functional deficits. Our findings reveal that Cdkl5 mutant mice exhibit impaired orientation selectivity, binocular integration, decreased neural signal amplitude, reduced neural coding ability, and network dysfunction, as observed through in vivo two-photon calcium imaging. Through a phospho-proteomics screen, we identify novel CDKL5 substrates. We further demonstrate that the absence of CDKL5 phosphorylation on the novel substrates leads to abnormal formation of RNA granules by affecting the dynamic process of liquid-liquid phase separation. Notably, deficits in the phosphorylation of the substrates alone are sufficient to induce cortical visual impairment similar to that observed in CDD. In summary, our study highlights circuit-specific cortical impairments in a CDD mouse model and uncovers a novel mechanism involving CDKL5. These findings provide insights into potential therapeutic strategies for CDD and shed light on the understanding of this complex neurodevelopmental disorder.