Functional interactions between anteroventral periventricular kisspeptin neurons and gonadotropin-releasing hormone neurons in female mice.

Kisspeptin neurons in the rostral hypothalamus are hypothesized to initiate preovulatory gonadotropin-releasing hormone (GnRH) surges by causing estradiol-dependent activation of GnRH neuron action potential firing and subsequent GnRH release. To determine if estradiol or ovarian cycle stage modulate functional connectivity in this circuit, anteroventral-periventricular (AVPV) area kisspeptin neurons were photostimulated while recording firing and/or evoked synaptic currents from preoptic area GnRH neurons in acutely-prepared mouse brain slices. Slices were prepared 2-days post ovariectomy (OVX) and OVX plus estradiol during the morning or afternoon, or in the afternoon on diestrus, proestrus, or 1-week post OVX, or 6-weeks post OVX with or without 1-week of estradiol replacement. Photostimulation induced a sustained, frequency-dependent increase in GnRH neuron firing rate. This neuromodulatory-typical response was not different in diestrous versus proestrous mice but was blunted in 1-week OVX mice, suggesting ovarian steroids are needed for maintenance. Neuromodulatory responses were infrequent in 6-week OVX mice with or without 1 week of estradiol treatment. A minority of GnRH neurons exhibited a rapid increase in firing rate typical of fast synaptic transmission. Monosynaptic connectivity was similarly low among hormonal states and consistently GABAergic. Interestingly, evidence of fast-synaptic transmission was not required for GnRH neurons to exhibit an increase in firing rate, suggesting neuromodulatory transmission can occur in this system without fast-synaptic co-transmission. Fast-synaptic transmission was, however, associated with greater increases in firing rate, but only during proestrus, indicating GnRH neuron responsiveness to AVPV kisspeptin neuron activation is dependent on both hormone milieu and synaptic connectivity.