Presynaptic Homeostatic Plasticity and Mental Health

ABSTRACT Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that stabilize neural function. It is widely hypothesized that homeostatic plasticity will be linked to the cause and/or severity of mental health disorders including autism and intellectual disability. In particular, homeostatic signaling systems are thought to constrain the physiological outcome of genetic or environmental perturbations that confer high risk for mental health disorders, thereby acting in a neuroprotective manner to preserve normal neuronal and circuit function. Yet, we are only beginning to understand the intersection of homeostatic plasticity and mental health. We recently demonstrated that the homeostatic regulation of presynaptic neurotransmitter release is expressed in the adult developing and adult mammalian brain. This form of homeostatic regulation controls both excitatory and inhibitory synaptic gain, thereby participating in the stabilization of excitation/inhibition balance, a process widely considered relevant to mental health. In this grant, we present new data regarding the molecular mechanisms of homeostatic plasticity in the mammalian brain, include genes previously assigned as high confidence risk factors for autism and intellectual disability. Our work establishes a mechanistic framework to associate homeostatic plasticity with the genetic underpinnings of mental health disorders. These data open the door to future therapeutic approaches to ameliorate the severity of mental health disorders based on the rational manipulation of homeostatic signaling.