Primary Cilia: A Novel Signaling Gateway To Neural Circuit Modulation

PROJECT SUMMARY
Primary cilium, a microtubule based antennae-like organelle, is present in every cortical
neuron, and when defective, leads to ciliopathies. A distinguishing feature of
ciliopathies is defective neural circuit formation and function. Disrupted construction
and function of neural circuits in ciliopathies lead to disorders such as autism,
intellectual disabilities, mood disorders, obesity, and epilepsy, thus implying a role for
primary cilia in neuronal function and circuit dynamics. Primary cilia signaling may
serve as a non­synaptic signaling mechanism through which environmental signals can
shape and refine neuronal circuits in health and disease. Nonetheless, how primary cilia
signaling sculpts neuronal circuit dynamics and whether primary cilia can be co-opted
as a therapeutic conduit to mend neural circuit malfunctions remain enigmatic. We aim
to resolve this challenge by defining the signaling mechanisms that are utilized by
primary cilia to enable appropriate neuronal functions necessary for the emergence and
maintenance of functional neural circuits in the brain. We will make this goal attainable
by leveraging the latest advances in optogenetic and chemogenetic interrogation of
signaling emanating from primary cilia, mapping neuronal ciliary receptome, profiling
ciliary connectome within human cerebral cortical circuitry, live imaging cilia driven
neuronal activity and transcriptional changes during neural circuit plasticity in living
animals, and modeling human ciliopathies in brain organoids with the aim of rescuing
circuit malfunctions using primary cilia as a tool. Collectively, this work will reveal how
primary cilia activity is transformed into changes in neuronal circuit function and the
pathways that must be successfully engaged to harness this insight in the service of
ameliorating neural circuit disorders. These outcomes will offer a transformative
opportunity to define new cellular principles of neural circuit formation and function
and will open up new therapeutic avenues of neural circuit correction.

Grant Number: 4RF1MH132710-04
NIH Institute/Center: NIH
Principal Investigator: EVA ANTON