The ubiquitin ligase UBR-1 regulates the synaptic strength between the GABAergic and glutamatergic signaling

Abstract

Excitation/Inhibition (E/I) balance is carefully maintained by the nervous system. Neurotransmitter GABA has been reported to be co-released with its sole precursor, another neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and Glutamatergic signaling have not fully elucidated. C. elegans DVB is a classically defined excitatory GABAergic motoneuron that drives the expulsion step in defecation motor program. We show that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter. UBR-1, a conserved ubiquitin ligase, regulates the DVB activity by suppressing a bidirectional inhibitory glutamate signaling. Loss of UBR-1 impairs the DVB Ca2+ activity and the expulsion frequency. These impairments are fully compensated by the knock-down of EAT-4 in DVB. Further, glutamate-gated chloride channels GLC-3 and GLC-2/4 receive DVBs glutamate signals to inhibit DVB and enteric muscle, respectively. These results implicate an intrinsic cellular mechanism that promotes the inherent asymmetric neural activity. We propose that the elevated glutamate in ubr-1 being the cause of the E/I shift, potentially contributes to the Johanson Blizzard Syndrome.