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Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice
Raffaele Mazziotti1, Leonardo Lupori2, Giulia Sagona1
1Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.
Abstract:
CDKL5 disorder is a neurodevelopmental disorder still without a cure. Murine models of CDKL5 disorder have been recently generated raising the possibility of preclinical testing of treatments. However, unbiased, quantitative biomarkers of high translational value to monitor brain function are still missing. Moreover, the analysis of treatment is hindered by the challenge of repeatedly and non-invasively testing neuronal function. We analyzed the development of visual responses in a mouse model of CDKL5 disorder to introduce visually evoked responses as a quantitative method to assess cortical circuit function. Cortical visual responses were assessed in CDKL5 null male mice, heterozygous females, and their respective control wild-type littermates by repeated transcranial optical imaging from P27 until P32. No difference between wild-type and mutant mice was present at P25-P26 whereas defective responses appeared from P27-P28 both in heterozygous and homozygous CDKL5 mutant mice. These results were confirmed by visually evoked potentials (VEPs) recorded from the visual cortex of a different cohort. The previously imaged mice were also analyzed at P60-80 using VEPs, revealing a persistent reduction of response amplitude, reduced visual acuity and defective contrast function. The level of adult impairment was significantly correlated with the reduction in visual responses observed during development. Support vector machine showed that multi-dimensional visual assessment can be used to automatically classify mutant and wt mice with high reliability. Thus, monitoring visual responses represents a promising biomarker for preclinical and clinical studies on CDKL5 disorder.
Insights
Visually evoked responses offer a new way to measure brain function in CDKL5 disorder models. This method can track disease progression and aid in developing treatments for this neurodevelopmental disorder.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- CDKL5 disorder is a severe neurodevelopmental condition lacking effective treatments.
- Current research lacks reliable biomarkers to track disease progression and treatment efficacy in preclinical models.
- Mouse models of CDKL5 disorder offer opportunities for therapeutic development, but require validated assessment tools.
Purpose of the Study:
- To establish visually evoked responses as a quantitative biomarker for assessing cortical circuit function in a CDKL5 disorder mouse model.
- To investigate the developmental trajectory of visual processing deficits in CDKL5 disorder.
- To evaluate the translational potential of visual response monitoring for preclinical and clinical studies.
Main Methods:
- Repeated transcranial optical imaging was used to assess cortical visual responses in CDKL5 mutant and wild-type mice from P27 to P32.
- Visually evoked potentials (VEPs) were recorded to confirm developmental and adult visual function.
- Support vector machine analysis was employed to assess the classification reliability of visual assessment.
Main Results:
- Defective visual responses emerged between P27-P28 in both heterozygous and homozygous CDKL5 mutant mice, not present earlier.
- Adult CDKL5 mutant mice exhibited persistent deficits in visual response amplitude, acuity, and contrast function.
- The degree of adult impairment correlated significantly with early-stage visual response reductions.
- Automated classification of mutant and wild-type mice using multi-dimensional visual assessment achieved high reliability.
Conclusions:
- Visually evoked responses serve as a sensitive and quantitative biomarker for CDKL5 disorder.
- This method allows for non-invasive, repeated assessment of neuronal function, crucial for preclinical drug testing.
- Monitoring visual responses shows significant promise for advancing therapeutic strategies for CDKL5 disorder.