Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α

Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β₂-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β₂-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.