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Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder
R Pizzo1, A Lamarca1, M Sassoè-Pognetto2
1Department of Neuroscience, University of Turin, Corso Massimo D'Azeglio 52, 10126 Turin, Italy.
Abstract:
Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD; however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). By using synapse-specific antibodies and confocal microscopy, we found that Cdkl5-KO mice display a lower density of TC synapses in the BC that was paralleled by a reduction of cortico-cortical (CC) connections compared to wild-type mice. These synaptic defects were accompanied by reduced BC activation, as shown by a robust decrease of c-fos immunostaining, and atypical behavioral responses to whisker-mediated tactile stimulation. Notably, a 2-day paradigm of enriched whisker stimulation rescued both number and configuration of excitatory synapses in Cdkl5-KO mice, restored cortical activity and normalized behavioral responses to wild-type mice levels. Our findings disclose a novel and unsuspected role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli. This article is part of a Special Issue entitled: Animal Models of Neurodevelopmental Disorders.
Insights
CDKL5 Deficiency Disorder impairs sensory processing by affecting synaptic connections in the brain. Enriched sensory stimulation can restore these connections and improve function in mouse models.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental condition caused by mutations in the CDKL5 gene.
- Disrupted sensory perception and processing are core symptoms of CDD, but their underlying mechanisms are poorly understood.
- The thalamo-cortical (TC) pathway is crucial for processing sensory information, including tactile input via whiskers.
Purpose of the Study:
- To investigate the impact of CDKL5 deficiency on synaptic organization and plasticity in the TC pathway of the barrel cortex (BC).
- To explore the role of CDKL5 in experience-dependent modifications of neural circuits.
- To understand how CDKL5 mutations contribute to sensory processing deficits in CDD.
Main Methods:
- Utilized synapse-specific antibodies and confocal microscopy to analyze synaptic density in Cdkl5-knockout (KO) and wild-type mice.
- Assessed cortical activation using c-fos immunostaining.
- Evaluated behavioral responses to whisker-mediated tactile stimulation.
- Implemented a 2-day enriched whisker stimulation paradigm.
Main Results:
- Cdkl5-KO mice exhibited reduced TC and cortico-cortical (CC) synaptic density in the BC compared to wild-type controls.
- Synaptic deficits correlated with decreased BC activation and atypical responses to tactile stimuli.
- Enriched whisker stimulation successfully rescued synaptic organization, restored cortical activity, and normalized behavioral responses in Cdkl5-KO mice.
Conclusions:
- CDKL5 plays a critical role in regulating the organization and experience-induced plasticity of excitatory connections in the barrel cortex.
- CDKL5 mutations disrupt higher-order processing of somatosensory stimuli by impairing synaptic function.
- Targeted sensory stimulation presents a potential therapeutic strategy for sensory deficits in CDD.
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