Developmental remodeling of circuit connectivity is a key process in shaping the mature
organization of neural circuits in the brain, optimizing their connectivity in order to perform specific
functions. Remodeling is triggered by both environmental stimuli and intrinsic genetic
mechanisms, and deficits in remodeling processes are thought to be a primary factor underlying
altered patterns of connectivity observed in a variety of neurodevelopmental and neuropsychiatric
disorders. Despite the clear importance of these developmental processes for normal brain
physiology and health, there are major gaps in our understanding of the cellular and molecular
mechanisms that regulate neural circuit remodeling.
Studies of genetic models have proven to be extremely fruitful for identifying fundamental
mechanisms underlying neural circuit development and function. Our previous studies have
pioneered new approaches for elucidating mechanisms for the specification of synaptic
connectivity in a genetically tractable model, the nematode Caenorhabditis elegans. During the
previous funding period, we demonstrated the remodeling of postsynaptic specializations located
on GABAergic neurons in the C. elegans motor circuit, and showed that the formation of new
synapses during remodeling is associated with the outgrowth of previously uncharacterized
spines on GABAergic dendrites. Moreover, we uncovered a novel mechanism required for spine
outgrowth and synapse assembly that depends on the synaptic organizer neurexin. These
findings demonstrate the strength of this system for identifying key genes with conserved roles in
shaping neural circuit connectivity and place us in a strong position for a deep investigation of in
vivo molecular mechanisms. Indeed, in preliminary studies supporting this application we have
identified the homeodomain transcription factor DVE-1, a homolog of mammalian chromatin
organizers SATB1/2, as a key hub for regulation of synapse elimination during remodeling of the
motor circuit. In Aim 1 of this proposal we investigate a novel transcriptional network controlling
synapse disassembly and elimination. In Aim 2, we explore cellular and molecular mechanisms
underlying the assembly of new synapses during circuit remodeling, focusing on the role of the
conserved synaptic organizer neurexin.
We expect that our studies of this experimentally tractable circuit in the worm will have a major
impact on our understanding of the molecular processes involved in circuit remodeling.
Additionally, we anticipate that the novel molecules and signaling mechanism we identify will be
excellent candidates for therapeutic intervention to treat neurodevelopmental disorders involving
disruptions in circuit connectivity.