BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure.

Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing -methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABA receptor (GABAR)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABAR agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABAR inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABAR activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABAR-α1 and K/Cl cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABAR signaling. We have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABA receptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABA receptor as well as KCC2 transporter immunoreactivity.