Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis

In mammals, stress elicits a stereotyped endocrine response that requires an increase in the activity of hypothalamic parvocellular neuroendocrine neurons. The output of these cells is normally constrained by powerful GABA-mediated synaptic inhibition. We found that acute restraint stress in rats released the system from inhibitory synaptic drive in vivo by down-regulating the transmembrane anion transporter KCC2. This manifested as a depolarizing shift in the reversal potential of GABA(A)-mediated synaptic currents that rendered GABA inputs largely ineffective. Notably, repetitive activation of GABA synapses after stress resulted in a more rapid collapse of the anion gradient and was sufficient to increase the activity of neuroendocrine cells. Our data indicate that hypothalamic neurons integrate psychological cues to mount the endocrine response to stress by regulating anion gradients.