A fresh look at kisspeptin neuron synchronization

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The arcuate kisspeptin neuron population in a coronal brain slice. Image courtesy of the Herbison laboratory




For many years, the ‘KNDy hypothesis’ has been the main mechanistic explanation of the pulsatile secretion of gonadotropin hormones. New research in Cell Reports proposes an alternative mechanism.

The arcuate nucleus kisspeptin (ARNKISS) neuronal network is a key part of the pulse generator. The KNDy hypothesis suggests that this network is regulated by an interplay between kisspeptin neurons and two coreleased neurotransmitters (neurokinin B and dynorphin). In this paper, the researchers used three approaches to investigate the mechanisms by which the ARNKISS neuronal network operates.

First, the researchers used GCaMP mini scopes in freely moving male mice to record the activation of each kisspeptin neuron during spontaneous synchronization events. “Then, to examine the contributions of key neurotransmitters and neuropeptides coreleased by ARNKISS neurons we developed a novel in vitro brain slice preparation,” explains author Paul Morris. This approach enabled the researchers to maintain spontaneous synchronizations within the neural network and to assess the effects of a range of receptor antagonists. Finally, the researchers used in vivo GCaMP fiber photometry coupled with microinfusion of the receptor antagonists directly into the ARN.

“It turns out that the key transmitter enabling the synchronized activity of kisspeptin neurons is the small amino acid transmitter glutamate,” explains author Su Young Han. Unlike what is predicted by the KNDy hypothesis, dynorphin controlled the frequency of glutamate-driven synchronization and neurokinin B facilitated the end-stage of synchronization. In addition, neither neurokinin B nor dynorphin was essential for ARNKISS neuron synchronization

“This study reframes a longheld hypothesis regarding the operation of a key hypothalamic central pattern generator,” concludes author Allan Herbison. “The mode of synchronization within the ARNKISS neural network is essential for normal fertility; we, therefore, expect that this significant advance in our understanding of the system will lead to future clinical treatments for infertility.” The researchers also highlight several areas for future research, such as determining whether the same mechanism is present in female mice and how the synchronization is turned off.

 

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Mechanism of kisspeptin neuron synchronization for pulsatile hormone secretion in male mice (2023)
Su Young Han, Paul G. Morris, Jae-Chang Kim, ..., Shel-Hwa Yeo, H. James McQuillan, Allan E. Herbison

SUMMARY

The mechanism by which arcuate nucleus kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to generate pulsatile hormone secretion remains unknown. An acute brain slice preparation maintaining synchronized ARNKISS neuron burst firing was used alongside in vivo GCaMP GRIN lens microendoscope and fiber photometry imaging coupled with intraARN microinfusion. Studies in intact and gonadectomized male mice revealed that ARNKISS neuron synchronizations result from near-random emergent network activity within the population and that this was critically dependent on local glutamate-AMPA signaling. Whereas neurokinin B operated to potentiate glutamate-generated synchronizations, dynorphin-kappa opioid tone within the network served as a gate for synchronization initiation. These observations force a departure from the existing ‘‘KNDy hypothesis’’ for ARNKISS neuron synchronization. A ‘‘glutamate two-transition’’ mechanism is proposed to underlie synchronizations in this key hypothalamic central pattern generator driving mammalian fertility.




Limitations of the study

A key limitation of the current study and proposed ‘‘glutamate two-transition’’ model is that the work has been undertaken in male mice. Although it is thought that pulse generator operation is fundamentally the same in males and females,4 it remains that future studies will need to ensure that the same mechanism operates in females. Equally, it will be important to evaluate whether the mechanism delineated here for mice is applicable to other species. Although there are rather few studies using the intra-ARN administration of receptor antagonists in relation to the pulse generator, results from the rat40 are very similar to those reported here for the mouse, while data from sheep41 differ in some respects.

In summary, we demonstrate here the key features of the synchronization mechanism used by the central pattern generator controlling GnRH secretion in male mice. We propose a substantial departure from the existing ‘‘KNDy hypothesis’’ with glutamate as the primary transmitter generating synchronization within the network and neuropeptides as neuromodulators; dynorphin in state-dependent synchronization initiation and NKB operating to potentiate the magnitude of synchronizations (Figure 7). Kisspeptin itself does not contribute to the synchronization mechanism but is used as the exclusive output signal to the GnRH neuron.56 It is expected that an accurate definition of GnRH pulse generator operation will be beneficial to the treatment of infertility in the clinic.

Figure 7. ‘‘Glutamate two-transition’’ model for ARNKISS neuron synchronization Stochastic, glutamate-dependent coupling between overlapping small groups of ARNKISS neurons (different colors) generates ongoing miniature synchronization episodes (mSEs). The first transition involves the emergence of a widespread population synchronization event (SE, pink) through exponential glutamate-driven self-excitation. The efficiency of this transition is modulated by dynorphin-kappa opioid tone within the network and also afferent inputs to the pulse generator that regulate its frequency of activity. The second transition involves the potentiation of already established synchronous activity by NKB increasing both the number of ARNKISS neurons involved in an SE and their individual levels of excitation. Intrinsic mechanisms are then likely involved in synchronization termination.