The G protein regulator AGS-3 allows C. elegans to alter behaviors in response to food deprivation.

Behavioral responses to food deprivation are a fundamental aspect of nervous system function in all animals. In humans, these behavioral responses prevent dieting from being an effective remedy for obesity. Several signaling molecules in the mammalian brain act through G proteins of the Gαi/o family to mediate responses to food restriction. The mechanisms for neural response to food deprivation may be conserved across species, allowing the power of genetic model organisms to generate insights relevant to the problem of human obesity. In a recent study, we found that C. elegans uses Gαo signaling to mediate a number of behavioral changes that occur after food deprivation. Food deprivation causes biochemical changes in the G Protein Regulator (GPR) domain protein AGS-3 and AGS-3, together with the guanine nucleotide exchange factor RIC-8, activates Gαo signaling to alter food-seeking behavior. These proteins are all conserved in the human brain. Thus the study of behavioral responses to food deprivation in C. elegans may reveal the details of conserved molecular mechanisms underlying neural responses to food deprivation.

AGS-3 alters Caenorhabditis elegans behavior after food deprivation via RIC-8 activation of the neural G protein G αo.

Proteins containing the G protein regulator (GPR) domain bind the major neural G protein Gα(o) in vitro. However, the biological functions of GPR proteins in neurons remain undefined, and based on the in vitro activities of GPR proteins it is unclear whether these proteins activate or inhibit G protein signaling in vivo. We found that the conserved GPR domain protein AGS-3 activates Gα(o) signaling in vivo to allow Caenorhabditis elegans to alter several behaviors after food deprivation, apparently so that the animals can more effectively seek food. AGS-3 undergoes a progressive change in its biochemical fractionation upon food deprivation, suggesting that effects of food deprivation are mediated by modifying this protein. We analyzed one C. elegans food-regulated behavior in depth; AGS-3 activates Gα(o) in the ASH chemosensory neurons to allow food-deprived animals to delay response to the aversive stimulus octanol. Genetic epistasis experiments show the following: (1) AGS-3 and the guanine nucleotide exchange factor RIC-8 act in ASH in a mutually dependent fashion to activate Gα(o); (2) this activation requires interaction of the GPR domains of AGS-3 with Gα(o); and (3) Gα(o)-GTP is ultimately the signaling molecule that acts in ASH to delay octanol response. These results identify a biological role for AGS-3 in response to food deprivation and indicate the mechanism for its activation of Gα(o) signaling in vivo.

Cytoplasmic polyadenylation element binding protein 1-mediated mRNA translation in Purkinje neurons is required for cerebellar long-term depression and motor coordination.

The ability of neurons to modify synaptic connections is critical for proper brain development and function in the adult. It is now clear that changes in synaptic strength are often accompanied by changes in synaptic morphology. This synaptic plasticity can be maintained for varying lengths of time depending on the type of neuronal activity that first induced the changes. Long-term synaptic plasticity requires the synthesis of new proteins, and one mechanism for the regulation of experience-induced protein synthesis in neurons involves cytoplasmic polyadenylation element binding protein (CPEB1). CPEB1 can bidirectionally regulate mRNA translation, first repressing translation, and then activating translation after the phosphorylation of two critical residues (T171 and S177). To determine the full extent of CPEB1-mediated protein synthesis in synaptic function, we engineered a line of mice expressing CPEB1 with these phosphorylation sites mutated to alanines (mCPEB1-AA) exclusively in cerebellar Purkinje neurons (PNs). Thus, mRNAs bound by mCPEB1-AA would be held in a translationally dormant state. We show that mCPEB1-AA localizes to synapses in cerebellum and resulted in a loss of protein synthesis-dependent phase of parallel fiber-PN long-term depression. This was accompanied by a change in spine number and spine length that are likely attributable in part to the dysregulation of IRSp53, a protein known to play a role in synaptic structure. Finally, mCPEB1-AA mice displayed a significant impairment of motor coordination and a motor learning delay.