Ionotropic Glutamate Receptors in the Paraventricular Nucleus (PVN) are Required to Trigger, but not Sustain, Sympathoexcitation by TNF alpha

Abstract

In the hypothalamic PVN, pro‐inflammatory cytokines (PIC) have been implicated in driving sympathetic nerve activity (SNA) in support of neurogenic hypertension. In other brain regions, tumor necrosis factor alpha (TNF‐a), a prototypical early onset PIC, has been reported to enhance glutamatergic neurotransmission by increasing membrane trafficking and expression of postsynaptic AMPA receptors leading to synaptic long‐term potentiation (LTP). Here, we tested if TNFa triggers such a response in the PVN to increase SNA. In anesthetized male rats (n=5), unilateral PVN injection (50 nl) of aCSF vehicle had no effect on splanchnic SNA (+2 ± 0.6 %), but rat recombinant TNFa (0.6 pmol) injected 10 minutes later elicited a progressive, ramp increase that averaged 52 ± 2 % (p<0.001, n=5). In separate rats (n=3), injection of TNFa after an Emax dose of the AMPA receptor antagonist NBQX (5.2 nmol) increased SNA by only 11 ± 1 %, which was significantly less than the control response (p<0.001). Because AMPA receptor‐mediated membrane potential depolarization can relieve Mg2+ block of NMDA receptors to potentiate postsynaptic responses to AMPA receptor activation, the effect of NMDA receptor blockade with an Emax dose of AP5 (24 nmol) was tested in another group of rats (n=3). TNFα after AP5 increased SNA by 19 ± 3 %, which was significantly less than the response following vehicle and not different from that following NBQX. Results indicate that AMPA and NMDA receptors in the PVN each participate in the TNFα‐induced increase of splanchnic SNA. Of note, neither NBQX or AP5 injection 30 minutes after TNFα altered the ramp‐like increase of SNA. Mechanisms that sustain progressive sympathoexcitation in response to TNFα in the PVN remain to be determined.Support or Funding InformationCapes (AAM, GRP), NIH HL088052 & AHA 25710176 (GMT)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.