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Published on: April 23, 2021
Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1
Grazia Della Sala1, Elena Putignano2, Gabriele Chelini1
1Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence.
Background:
CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical Rett syndrome. CDKL5 was shown to interact with synaptic proteins, but an in vivo analysis of the role of CDKL5 in dendritic spine dynamics and synaptic molecular organization is still lacking.
Methods:
In vivo two-photon microscopy of the somatosensory cortex of Cdkl5(-/y) mice was applied to monitor structural dynamics of dendritic spines. Synaptic function and plasticity were measured using electrophysiological recordings of excitatory postsynaptic currents and long-term potentiation in brain slices and assessing the expression of synaptic postsynaptic density protein 95 (PSD-95). Finally, we studied the impact of insulin-like growth factor 1 (IGF-1) treatment on CDKL5 null mice to restore the synaptic deficits.
Results:
Adult mutant mice showed a significant reduction in spine density and PSD-95-positive synaptic puncta, a reduction of persistent spines, and impaired long-term potentiation. In juvenile mutants, short-term spine elimination, but not formation, was dramatically increased. Exogenous administration of IGF-1 rescued defective rpS6 phosphorylation, spine density, and PSD-95 expression. Endogenous cortical IGF-1 levels were unaffected by CDKL5 deletion.
Conclusions:
These data demonstrate that dendritic spine stabilization is strongly regulated by CDKL5. Moreover, our data suggest that IGF-1 treatment could be a promising candidate for clinical trials in CDKL5 patients.
Insights
Cyclin-dependent kinase-like 5 (CDKL5) regulates dendritic spine stabilization. Insulin-like growth factor 1 (IGF-1) treatment shows promise for restoring synaptic deficits in CDKL5-related neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in CDKL5 (cyclin-dependent kinase-like 5) are linked to severe neurodevelopmental disorders, including atypical Rett syndrome.
- While CDKL5 interacts with synaptic proteins, its in vivo role in dendritic spine dynamics and synaptic organization remains unclear.
Purpose of the Study:
- To investigate the in vivo role of CDKL5 in dendritic spine dynamics and synaptic molecular organization.
- To assess the therapeutic potential of IGF-1 in ameliorating synaptic deficits in CDKL5 deficiency.
Main Methods:
- In vivo two-photon microscopy of the mouse somatosensory cortex to monitor dendritic spine structural dynamics.
- Electrophysiological recordings to measure synaptic function and plasticity (long-term potentiation).
- Assessment of postsynaptic density protein 95 (PSD-95) expression and impact of IGF-1 treatment.
Main Results:
- CDKL5-deficient mice exhibited reduced spine density, fewer persistent spines, and impaired long-term potentiation.
- Juvenile mutants showed increased short-term spine elimination.
- IGF-1 treatment rescued synaptic deficits, including spine density and PSD-95 expression.
Conclusions:
- CDKL5 plays a critical role in dendritic spine stabilization.
- IGF-1 treatment represents a potential therapeutic strategy for CDKL5 patients.
