Grant: Project Grant

Primary cilia are hair-like, signaling antenna protruding from all neurons. In the past decade, primary cilia have sparked enormous interest due to the discoveries that mutations in over 150 genes that encode ciliary proteins can lead to 30+ human rare disorders collectively termed "ciliopathies". The brain is particularly vulnerable to impaired primary cilia. Patients of ciliopathies show deficits such as ataxia, developmental dyslexia, and are often diagnosed with intellectual disability, autism spectrum disorders, and schizophrenia. Currently, our understanding of primary cilia in the brain is mostly confined to early neuronal development. The postnatal brain development is a lengthy process, during when neurons dedicate major energy forming synaptic activity. Particularly, the adolescent stage is a critical brain developmental period characterized by the peak of synaptic growth and maturation. Thus, we ask key questions in this proposal: Is there a continued and specific requirement of primary cilia for proper synaptic development in the adolescent brain? If so, what are the cilia-driven signaling mechanisms that regulate synaptic development? Hypothesis: Neuronal primary cilia act as signaling hubs to provide a critical layer of modulation to synaptic formation and function. Using ciliopathy mouse models, we will: Aim 1. Determine the role of primary cilia in synaptic development. Aim 2. Identify the primary cilia signaling receptors that modulate synapses. Aim 3. Define the cilia-driven downstream molecular mechanisms in synaptic modulation. This work will yield transformative insights into ciliopathies pathology and illuminate a previously unknown mechanism central for neuronal developmental program.