Molecular recognition strategies for wiring neurons into circuits

In the developing nervous system, an enormous number and diversity of neurons are precisely organized into neural circuits. How can such a vast set of neural connections be wired using limited cues encoded in our genomes? To tackle this problem, we are studying a family of neuronal receptors with an extraordinary potential for conferring cell-surface diversity and wiring specificity. The clustered Protocadherin genes (Pcdhs) are tandemly arrayed on a single genomic locus and encode ~60 cadherin-related transmembrane proteins that are combinatorially expressed among single neurons and engage in homophilic interactions. We propose that the Pcdhs serve as a code for ‘neuron individuality’ to mediate complex patterns of connectivity. By focusing on simpler circuits in the mouse retina and manipulating the clustered Pcdh locus in mouse models, we have shown that the Pcdhs provide a self/non-self recognition code for neurite patterning. I will discuss our ongoing work on the roles of Pcdh isoform diversity in neurite patterning, and our recent findings that the Pcdhs regulate the survival of GABAergic inhibitory interneurons throughout the brain. Deletion of Pcdhs in inhibitory neurons in mice, rather than in excitatory neurons, has profound consequences on postnatal survival, motor behaviours, and leads to epileptic seizures. These studies will yield new insights on the local cell-cell interactions and molecular cues that establish the proper balance and wiring of inhibitory cells into circuits.