UCSF

Brain function is remarkably stable throughout the many years of adult life even in the face of continuous internal and external change. Homeostatic plasticity is hypothesized to support this stability by constraining neuronal activity within a range appropriate for a neuron’s participation in neural circuits and meaningful information transfer. Presynaptic homeostatic potentiation (PHP) is one form of homeostatic plasticity acting in both peripheral and central synapses and is conserved from insects to humans. Here we describe the function of an innate immune receptor, PGRP-LC, and its downstream signaling pathway in controlling PHP. Innate immunity is known to function in the brain where it modifies the structure of synapses and circuits during development, as well responding to and controlling neuronal activity during adulthood. This is the first evidence implicating innate immunity in presynaptic function. First, we show that PGRP-LC functions as a presynaptic receptor during the induction and expression of PHP, through modulation of the readily releasable pool of synaptic vesicles. Next, we interrogate the canonical innate immune signaling pathway downstream of PGRP-LC, testing four downstream genes for function in PHP. In so doing, we find evidence that this pathway is reorganized to support the specialized structure and function of neurons, and the needs of PHP. Last, we characterize in detail the function of a kinase in the pathway, Tak1, in controlling synaptic vesicle release probability. Our data lead us to propose a model where Tak1 acts to stabilize synaptic vesicles close to the active zone by inhibiting a de-priming or de-docking process. Therefore, we have implicated a novel kinase in regulation of neurotransmitter release. We expect that innate immune signaling through PGRP-LC then modulates the function of Tak1 during PHP to achieve potentiation of vesicle release. Overall, our data speak to the importance of innate immune signaling in neurons specifically, as they undergo changes during their otherwise normal day-to-day activity.