Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

• Published in: Biological psychiatry (1969) 2016-08, Vol.80 (4), p.302-311
• Main Authors: Della Sala, Grazia, Putignano, Elena, Chelini, Gabriele, Melani, Riccardo, Calcagno, Eleonora, Michele Ratto, Gian, Amendola, Elena, Gross, Cornelius T, Giustetto, Maurizio, Pizzorusso, Tommaso
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Animals, Newborn; CDKL5; dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - pathology; Disease Models, Animal; Disks Large Homolog 4 Protein; Epileptic Syndromes; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Guanylate Kinases - metabolism; IGF-1; imaging; Insulin-Like Growth Factor I - therapeutic use; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Patch-Clamp Techniques; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; PSD-95; Psychiatry; Pyramidal Cells - pathology; Pyramidal Cells - ultrastructure; Rett syndrome; Rett Syndrome - drug therapy; Rett Syndrome - genetics; Rett Syndrome - pathology; Somatosensory Cortex - pathology; Spasms, Infantile - drug therapy; Spasms, Infantile - genetics; Spasms, Infantile - pathology; Synapses - drug effects; Synapses - pathology
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2015.08.028

Abstract 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 Cdkl 5−/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.