Mechanisms of activity-dependent regulation of neurotransmitter switching in the developing and mature nervous system

We are intrigued by how electrical and intracellular calcium activity of neurons can regulate neurotransmitter switching, a newly recognized form neuroplasticity, during development and in the mature nervous system.In the developing Xenopus spinal cord, newly born neurons exhibit characteristic spontaneous calcium activity during a critical period that leads to the specification of distinct neurotransmitter phenotypes, such as glutamate and GABA. Altering electrical and calcium activity of these spinal neurons in vitro and in vivo causes homeostatic re-specification of neurotransmitters. Here we investigated the molecular mechanism by which neuronal activity regulates transmitter re-specification. We demonstrated that neuronal activity acts non-cell-autonomously through the release of brain-derived neurotrophic factor (BDNF) to regulate a glutamate/GABA selector transcription factor tlx3 through activation of a TrkB/MAPK signaling pathway.We then investigated the role of neuronal activity in transmitter switching in the adult mammalian brain. In the adult rat following long-day photoperiod exposure, the number of dopaminergic neurons decreases while the number of somatostatin neurons increases in the paraventricular nucleus of hypothalamus (PaVN), causing anxiety and depression-like behaviors. Here we demonstrated that long-day photoperiod exposure increases neuronal activity of PaVN dopaminergic neurons prior to transmitter switch. Blocking activity of PaVN dopaminergic neurons abolishes their transmitter switch in response to long-day photoperiod exposure, suggesting an activity-dependent cell-population-autonomous mechanism