Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein

Abstract

SUMMARY Neural circuits are actively remodeled during brain development but the molecular mechanisms that trigger circuit refinement are poorly understood. Here we describe a transcriptional program in C. elegans that regulates expression of an Ig domain protein, OIG-1, to control the timing of synaptic remodeling. DD GABAergic neurons reverse polarity during larval development by exchanging the locations of pre- and postsynaptic components. In newly born larvae, DDs receive cholinergic inputs in the dorsal nerve cord. These inputs are switched to the ventral side by the end of the first larval (L1) stage. VD class GABAergic neurons are generated in the late L1 and are postsynaptic to cholinergic neurons in the dorsal nerve cord but do not remodel. We investigated remodeling of the postsynaptic apparatus in DD and VD neurons using targeted expression of the acetylcholine receptor (AChR) subunit, ACR-12::GFP. We determined that OIG-1 antagonizes the relocation of ACR-12 from the dorsal side in L1 DD neurons. During the L1/L2 transition, OIG-1 is down-regulated in DD neurons by the transcription factor, IRX-1/Iroquois, allowing the repositioning of synaptic inputs to the ventral side. In VD class neurons, which normally do not remodel, the transcription factor UNC-55/COUP-TF turns off IRX-1, thus maintaining high levels of OIG-1 to block the removal of dorsally-located ACR-12 receptors. OIG-1 is secreted from GABA neurons but its anti-plasticity function is cell-autonomous but may not require secretion. Our study provides a novel mechanism by which synaptic remodeling is set in motion through regulated expression of an Ig domain protein.

Neural circuit rewiring: insights from DD synapse remodeling

“…Indeed, an example of synapse refinement in the absence of axon growth was described in the mammalian central nervous system, where imaging of individual axonal arbors of retinal ganglion cells showed that retinogeniculate synapse remodeling can occur without axon retraction. 33 Four decades after John White's seminal work, we have learned a great deal about DD remodeling, which has provided a rich platform to study the temporal cues 4,6,7,9,10,14,17 as well as the cellular mechanisms that underlie this complete inversion of synaptic connectivity. [22][23][24] Our findings have also revealed a novel role of dynamic MTs in regulating synaptic vesicle transport in the absence of neurite growth or pruning.…”

“…17 In L1 animals, the post-synaptic GABA-A receptor UNC-49 is expressed exclusively in the ventral muscles. 18 Following the birth of the VD neurons in L2 animals, UNC-49 receptor clusters appear in both ventral and dorsal muscles.…”

Myrf ER-Bound Transcription Factors Drive C. elegans Synaptic Plasticity via Cleavage-Dependent Nuclear Translocation

“…A second, Ig-domain containing, gene, oig-1 , was recently found to be a transcriptional target of LIN-14. OIG-1 functions as a synaptic organizer to maintain DD’s early synaptic pattern (He et al, 2015; Howell et al, 2015). Loss of oig-1 results in premature rewiring of DD neurons, partially resembling lin-14 null.…”

Excitatory neurons sculpt GABAergic neuronal connectivity in the C. elegans motor circuit

“…The nicotinic AChR subunit ACR-12 is a constituent of GABA neuron iAChRs. ACR-12::GFP clusters localize opposite ACh release sites and relocate appropriately during developmental remodeling, suggesting that these clusters report mature postsynaptic structures (Petrash et al, 2013;He et al, 2015). We examined the distribution of ACR-12:: GFP in the dorsal nerve cord where the majority of chemical synaptic inputs to VD neurons occur (VD synaptic contacts with muscles are exclusively ventral) (White et al, 1986).…”