Optogenetic Stimulation of Arcuate Nucleus Kiss1 Neurons Reveals a Steroid-Dependent Glutamatergic Input to POMC and AgRP Neurons in Male Mice

Apr 20, 2016Molecular endocrinology (Baltimore, Md.)

Stimulating Hormone-Sensing Neurons Shows Hormone-Dependent Excitatory Signals to Appetite-Control Neurons in Male Mice

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Abstract

Castrated male mice showed higher mRNA levels for Kiss1 and vesicular glutamate transporter 2 in Kiss1(ARC) neurons compared to gonad-intact males.

Kiss1(ARC) neurons connect with POMC and AgRP neurons, suggesting they may influence energy balance.
Single-cell analysis indicated that 100% of Kiss1(ARC) neurons expressed mRNAs for Kiss1, while 88% expressed mRNAs for vesicular glutamate transporter 2.
Low frequency stimulation of Kiss1(ARC) neurons produced a fast glutamatergic response in POMC and AgRP neurons.
Castrated male mice exhibited greater glutamate release in POMC and AgRP neurons compared to gonad-intact males during paired-pulse stimulation.
Group I and group II metabotropic glutamate receptor agonists affected POMC and AgRP neurons differently, reflecting varied synaptic inputs from Kiss1(ARC) neurons.

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Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. Proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, located in the arcuate nucleus (ARC) of the hypothalamus, integrate numerous excitatory and inhibitory inputs to ultimately regulate energy homeostasis. Given that POMC and AgRP neurons are contacted by Kiss1 neurons in the ARC (Kiss1(ARC)) and they express androgen receptors, Kiss1(ARC) neurons may mediate the orexigenic action of testosterone via POMC and/or AgRP neurons. Quantitative PCR analysis of pooled Kiss1(ARC) neurons revealed that mRNA levels for Kiss1 and vesicular glutamate transporter 2 were higher in castrated male mice compared with gonad-intact males. Single-cell RT-PCR analysis of yellow fluorescent protein (YFP) ARC neurons harvested from males injected with AAV1-EF1α-DIO-ChR2:YFP revealed that 100% and 88% expressed mRNAs for Kiss1 and vesicular glutamate transporter 2, respectively. Whole-cell, voltage-clamp recordings from nonfluorescent postsynaptic ARC neurons showed that low frequency photo-stimulation (0.5 Hz) of Kiss1-ChR2:YFP neurons elicited a fast glutamatergic inward current in POMC and AgRP neurons. Paired-pulse, photo-stimulation revealed paired-pulse depression, which is indicative of greater glutamate release, in the castrated male mice compared with gonad-intact male mice. Group I and group II metabotropic glutamate receptor agonists depolarized and hyperpolarized POMC and AgRP neurons, respectively, which was mimicked by high frequency photo-stimulation (20 Hz) of Kiss1(ARC) neurons. Therefore, POMC and AgRP neurons receive direct steroid- and frequency-dependent glutamatergic synaptic input from Kiss1(ARC) neurons in male mice, which may be a critical pathway for Kiss1 neurons to help coordinate energy homeostasis and reproduction.

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Optogenetic Stimulation of Arcuate Nucleus Kiss1 Neurons Reveals a Steroid-Dependent Glutamatergic Input to POMC and AgRP Neurons in Male Mice

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