Hyperpolarization-Activated Currents in Gonadotropin-Releasing Hormone (GnRH) Neurons Contribute to Intrinsic Excitability and Are Regulated by Gonadal Steroid Feedback

Abstract

Pulsatile release of gonadotropin-releasing hormone (GnRH) is required for fertility and is regulated by steroid feedback. Hyperpolarization-activated currents (I h ) play a critical role in many rhythmic neurons. We examined the contribution of I h to the membrane and firing properties of GnRH neurons and the modulation of this current by steroid milieu. Whole-cell voltage-and currentclamp recordings were made of GFP-identified GnRH neurons in brain slices from male mice that were gonad-intact, castrated, or castrated and treated with estradiol implants. APV, CNQX, and bicuculline were included to block fast synaptic transmission. GnRH neurons (47%) expressed a hyperpolarization-activated current with pharmacological and biophysical characteristics of I h . The I hspecific blocker ZD7288 reduced hyperpolarization-induced sag and rebound potential, decreased GnRH neuron excitability and action potential firing, and hyperpolarized membrane potential in some cells. ZD7288 also altered the pattern of burst firing and reduced the slope of recovery from the after-hyperpolarization potential. Activation of I h by hyperpolarization increased spike frequency, whereas inactivation of I h by depolarization reduced spike frequency. Castration increased I h compared with that in gonad-intact males. This effect was reversed by in vivo estradiol replacement. Together, these data indicate I h provides an excitatory drive in GnRH neurons that contributes to action potential burst firing and that estradiol regulates I h in these cells. As estradiol is the primary central negative feedback hormone on GnRH neuron firing in males, this provides insight into the mechanisms by which steroid hormones potentially alter the intrinsic properties of GnRH neurons to change their activity.

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…HCN3 channels are expressed in the soma of IGL neurons (Fig. 1), and our data are consistent with previous observations demonstrating that block of I h decreases somatic, but not dendritic, excitability in several brain regions (Maccaferri and McBain, 1996;Lüthi et al, 1998;Saitow and Konishi, 2000;Neuhoff et al, 2002;Chu et al, 2010).…”

“…A, Intrinsic temporal summation producing burst firing was initiated by intracellular injection of a train containing five current pulses (100 pA); the protocol shown at bottom was previously described (Ying et al, 2005). EPSC-shaped current pulses were generated with the following function: I(t) ϭ A ϫ (1 Ϫ e Ϫt/ rise ) n e Ϫt/ decay , where A is the infinite time amplitude of the current (in picoamperes), n is an integer, and rise (0.5 ms) and decay (5 ms) are rising and falling time constants, respectively (Magee, 1998) al., Chu et al, 2010;Dembrow et al, 2010). The underlying mechanisms for these effects remain unclear, although Chu et al (2010) suggest that the change is likely due to alteration in other voltagedependent conductances.…”

“…EPSC-shaped current pulses were generated with the following function: I(t) ϭ A ϫ (1 Ϫ e Ϫt/ rise ) n e Ϫt/ decay , where A is the infinite time amplitude of the current (in picoamperes), n is an integer, and rise (0.5 ms) and decay (5 ms) are rising and falling time constants, respectively (Magee, 1998) al., Chu et al, 2010;Dembrow et al, 2010). The underlying mechanisms for these effects remain unclear, although Chu et al (2010) suggest that the change is likely due to alteration in other voltagedependent conductances. Since PIP 2 can influence other ion channels (Suh and Hille, 2008), it is possible that PIP 2 -induced depolarization observed here might involve enhancing depolarizing conductance(s) and/or decreasing hyperpolarizing ones as seen in microvillar photoreceptors (del Pilar Gomez and Nasi, 2005).…”

Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle

“…2F), suggesting that decreased GnRH release due to estradiol alleviates GnRHR neuronal burst activity. The direct effect of the estradiol-generated tonicity of GnRHR neuron firing could result from the prevention of intrinsic cascades known to induce oscillatory spike behavior (Bal et al 1995;Chu et al 2010) or by the modulation of local network activity by estradiol (Christian and Moenter 2007;Veliskova and Velisek 2007). Estradiol is well known as an initiator of burst activity (Abe and Terasawa 2005;Chu et al 2009), but such a scenario seems unlikely here.…”

A Computational Model of the Dendron of the GnRH Neuron

“…For instance, VIP current is an important current induced by neuromodulators (i.e., extrinsic inputs) (Gerhold et al 2005;Gerhold and Wise 2006;Christian and Moenter 2008). VIP could activate hyperpolarization-activated current (I h ) to modulate action potential burst firing, acting through cAMP (Gerhold et al 2005;Chu et al 2010). I h could also affect the afterhyperpolarization potential (AHP), which is important for the control of bursting, and may interact with the afterdepolarization potentials (ADP) current to modulate action potential firing (Chu et al 2010).…”