Cyclin-dependent kinase-like 5 (CDKL5) syndrome is a neurodevelopmental disorder characterized by early-onset intractable seizures, mental retardation, and hand stereotypies. Studies have shown that loss of CDKL5 protein function is responsible for aberrations in neuronal morphogenesis, and decreased synaptogenesis. In order to understand the effects of CDKL5 mutations on human neural disease pathology, we utilized induced pluripotent stem cell (iPSC) technology to generate human iPSC-derived neurons from CDKL5 patients. Furthermore, to circumvent in vitro iPSC disease modeling limitations and to take advantage of an in vivo brain environment, we integrated these two systems by engrafting human iPSC-derived neural progenitor cells (NPCs) into immunodeficient mice. Here, we report defects in neuronal morphology in CDKL5- mutant neurons differentiated in vitro that are retained in human neurons differentiated in a mouse brain. Furthermore, we found that using a histone deacetylase inhibitor, LMK235, specific to histone deacetylase 4 (HDAC4), was able to rescue defects in synaptogenesis and neural electrical activity in CDKL5 iPSC-derived neurons in vitro. Ultimately, we hope our work will provide further insights into CDKL5 disease pathology and accelerate the development of treatments for this complex neurodevelopmental disorder.