Animals constantly update their behavior by evaluating the significance of current sensory input and then integrating this information with knowledge gained from prior experiences. To filter irrelevant input and focus attention towards high priority stimuli, all animals exploit a fundamental form of learning, called habituation. Habituation is observed by a progressive response decline to repeatedly experienced, yet insignificant stimuli and provides a behavioral measure of a neural circuit’s ability to balance synaptic excitation, inhibition, and plasticity. Habituation deficits are observed in schizophrenia, autism, and addiction, and contribute strongly to the patients’ overall dysfunction. Despite its conservation and clinical relevance, the genetic and cellular mechanisms that mediate habituation remain poorly understood.
To identify genes critical for habituation, we recently performed an unbiased, genome-wide screen for zebrafish mutants with reduced habituation of the acoustic startle response. This screen identified a functional gene set for habituation, including a gene previously unknown for a role in habituation: pyruvate carboxylase a. Pyruvate carboxylase (PC) is a mitochondrial enzyme that converts pyruvate to oxaloacetate to stimulate the TCA cycle, and hence, the synthesis of metabolic products with diverse biological functions. In the brain, PC is not thought to be active in neurons, but instead, functions in oligodendrocytes to promote myelination and in astrocytes to replenish neurons with neurotransmitters. Although both glial cell types are known to support synaptic plasticity, it remains unclear how signaling pathways in either cell type directly regulate habituation.
Through molecular-genetic, pharmacological, and behavioral analyses, we will provide data showing that astrocytic PC activity supports glutamatergic neurotransmission to promote habituation. This work defines a novel molecular mechanism underlying habituation and reveals a novel cellular locus of plasticity for habituation: astrocytes!