title: Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice.
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.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Mazziotti
authors.affiliation: BIO@SNS Lab, Scuola Normale Superiore via Moruzzi, 1?56124 Pisa, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lupori
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sagona
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.|Institute of Neuroscience, National Research Council, via Moruzzi, 1 56124 Pisa, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Gennaro
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.|Institute of Neuroscience, National Research Council, via Moruzzi, 1 56124 Pisa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Della Sala
authors.affiliation: Institute of Neuroscience, National Research Council, via Moruzzi, 1?56124 Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Putignano
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Area San Salvi - Pad. 26, 50135 Florence, Italy.|BIO@SNS Lab, Scuola Normale Superiore via Moruzzi, 1 56124 Pisa, Italy.|Institute of Neuroscience, National Research Council, via Moruzzi, 1 56124 Pisa, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
mesh_terms: D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D000073376:Epileptic Syndromes; D005074:Evoked Potentials, Visual; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D014786:Vision Disorders / Q000503:physiopathology; D014792:Visual Acuity; D014793:Visual Cortex / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017346:Protein Serine-Threonine Kinases