Determining the Impact of Callosal Connectivity on Visual Cortical Structure and Cortical Visual Impairment in Cdkl5 Deficiency Disorder - PROJECT SUMMARY/ABSTRACT
One of the leading causes of visual dysfunction in developed countries is cortical visual impairment (CVI). CVI
is very commonly a comorbidity with neurological and neurodevelopmental disorders, and significantly
contributes to altered development. CVI occurs when deficits in the eyes alone cannot explain the defects in
perception, indicating that visual processing in the cortex is responsible for altered visual function. No
treatments or effective therapies are currently available. Elucidating the circuitry underlying CVI in
neurodevelopmental disorders will guide in designing targeted treatments not only for visual impairment, but
also to improve other core features of neurological functioning. One neurodevelopmental disorder with high
rates of CVI is CDKL5 deficiency disorder (CDD). CDD is an epileptic encephalopathy characterized by
seizures beginning in the first months of life, severe developmental delay, often including lack of speech and
independent walking. About 75% of individuals with CDD experience CVI and this impairment is also reflected
in mouse models of CDD which have been shown to have reduced visual evoked response and reduced visual
acuity. Although CVI is a prominent feature of CDD, we do not understand how CVI arises and the underlying
circuits. Recently, our laboratory discovered that CDD mouse models exhibit an increased functional callosal
connectivity across cortical hemispheres. Callosal interhemispheric connectivity is key for higher order
processing. In neurotypical development, callosal projection neurons (CPNs) prune their axons from layer 4
pyramidal neurons and refine selective synapses in superficial and deeper cortical layers allowing the
acquisition of adult visual function. Our hypothesis is that in the absence of CDKL5, callosal projections
fail to refine and to acquire proper mature function giving rise to CVI. By combining a multi-level
approach, I will test this working hypothesis in two aims. In aim one I will analyze anatomically the number, cell
type, and distribution of CPNs and their synaptic partners in Cdkl5 knockout mice. Training for this aim will be
provided by imaging core facilities and Dr. Michela Fagiolini who is an expert in visual cortical structure and
development. In aim two I will examine physiologically the neuronal activity and dynamics of visual cortical
circuits with and without modulation of CPNs in the visual cortex of freely behaving Cdkl5 knockout and
littermate WT mice. Training for this aim will be overseen by Dr. Michela Fagiolini, as well as the animal
behavior and physiology core. Additional mentorship will be provided by Dr. Heather Olson as the head of
CDKl5 clinic at Boston Children’s Hospital and by Dr. Bo Zhang on statistical technique and rigor. Together
these aims will provide critical insight into the role of interhemispheric connectivity in cortical visual impairment
in CDD opening the door to innovations in therapeutics.
