This study provides compelling evidence for the essential role of CDKL5 in the adult brain, showing that its selective deletion in glutamatergic neurons of the forebrain, even after the completion of brain development, is sufficient to induce neuroanatomical, synaptic, and behavioral alterations that are characteristic of the CDKL5 deficiency disorder (CDD) phenotype. The gene discussed is CDKL5; the disease is craniodiaphyseal dysplasia.