Disentangling the roles of endoplasmic reticulum stress and activity in the peripheral olfactory circuit

PROJECT SUMMARY Olfactory dysfunction is a frequent sign of insidious neurological disease, likely due to the delicate molecular mechanisms required to maintain a functioning sense of smell. Olfactory sensory neurons stochastically express a single odorant receptor gene out of ~1000 in the mouse. The expressed odorant receptor then specifically drives olfactory neuron axons to a unique and stereotyped position in the olfactory bulb called a glomerulus, forming a spatial map of glomeruli which each represent just one odorant receptor. The molecular mechanism that pairs odorant receptor identity with glomerular target has remained disputed. Several experiments have shown that neuronal activity can elicit major changes in the transcription of axon guidance molecules. More recently, studies from our lab have implicated endoplasmic reticulum stress signaling as the critical variable for proper glomerular targeting. Interestingly, several genes that are upregulated by neuronal activity are downregulated by endoplasmic reticulum stress, and vice-versa. We are proposing to systematically disentangle the effects of endoplasmic reticulum stress and olfactory sensory neuron activity at different timepoints across the lifetime of olfactory neurons. We first aim to test the effects of endoplasmic reticulum stress on axon guidance programs in immature olfactory sensory neurons. Next, we aim to uncover the molecular mechanism(s) that are responsible for the inverse effects of endoplasmic reticulum stress and neuronal activity on gene expression. Finally, we propose to test the effects of endoplasmic reticulum stress on synaptic function in mature olfactory sensory neurons. Our findings could have broad implications for the development and maintenance of neurological circuits, beyond the olfactory system.