Role of a calcium-binding neuronal protein in regulating locomotion in a worm model
18 Apr 2018
By Dr. Kavita Babu, Intermediate Fellow
Indian Institute of Science Education and Research (IISER) Mohali
A functional nervous system requires strength from two pillars that form the basis of synaptic transmission; excitation and inhibition. Excitatory signals from presynaptic cells to postsynaptic cells make the latter more likely to fire, while inhibitory signals decrease the probability of firing in the postsynaptic cells. An imbalance in excitatory and inhibitory signaling has been reported to be a factor in the pathogenesis of several neurological disorders like Alzheimer’s disease, autism spectrum disorders and epileptic seizures. The neuromuscular junction (NMJ) of the tiny nematode worm, C. elegans receives synaptic inputs from both excitatory and inhibitory motor neurons, thus making it an excellent system to study the balance between excitation and inhibition.
We have characterized an isoform specific role for a calcium-binding protein, Calsyntenin, CASY-1 in maintaining this balance at the NMJ. The shorter isoforms of CASY-1; CASY-1B and C contain the conserved C-terminus of mammalian Calsyntenins. We show that the shorter isoforms regulate the release of the inhibitory neurotransmitter GABA from GABAergic motor neurons. CASY-1B/C interact with the motor protein UNC-104/KIF1A and allow for the normal trafficking of GABA synaptic vesicles, thus modulating GABA release at the NMJ (Thapliyal et al., 2018b). GABA acts as one of the major inhibitory neurotransmitters in both vertebrate and invertebrate nervous system.
We also show that the longer CASY-1A isoform, which contains all the conserved domains of mammalian Calsyntenins, modulates the activity of sensory neurons by regulating stable release of the neurotransmitter, Glutamate (Thapliyal et al., 2018a). Glutamate release in turn has been shown to maintain normal release of the excitatory neurotransmitter acetylcholine at the NMJ (Choi et al., 2013; Choi et al., 2015).
In light of this work, we hypothesize that in the absence of casy-1, the balance between excitation and inhibition at the NMJ is disturbed, resulting in altered locomotary behavior. Restoring this balance by expressing CASY-1B/C in GABAergic motor neurons or CASY-1A in sensory neurons completely restores the movement defects seen in casy-1 mutants.
Our study illustrates a novel role for C. elegans ortholog of mammalian Calsyntenins in regulating excitation-inhibition balance at the NMJ (see illustration). Mammalian Calsyntenins have been implicated in the pathogenesis of several neurological disorders. Thus, future investigations in this area could enhance our understanding about pathophysiological mechanisms that trigger Calsyntenin related brain disorders.
Choi, S., Chatzigeorgiou, M., Taylor, K.P., Schafer, W.R., and Kaplan, J.M. (2013). Analysis of NPR-1 reveals a circuit mechanism for behavioral quiescence in C. elegans. Neuron 78, 869-880.
Choi, S., Taylor, K.P., Chatzigeorgiou, M., Hu, Z., Schafer, W.R., and Kaplan, J.M. (2015). Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release. PLoS genetics 11, e1005359.
Thapliyal, S., Ravindranath, S., and Babu, K. (2018a). Regulation of Glutamate Signaling in the Sensorimotor Circuit by CASY-1A/Calsyntenin in Caenorhabditis elegans. Genetics 208, 1553-1564.
Thapliyal, S., Vasudevan, A., Dong, Y., Bai, J., Koushika, S.P., and Babu, K. (2018b). The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction. PLoS genetics 14, e1007263.