Elsevier

Peptides

Volume 30, Issue 1, January 2009, Pages 16-25
Peptides

Review
The role of kisspeptin and GPR54 in the hippocampus

https://doi.org/10.1016/j.peptides.2008.07.023Get rights and content

Abstract

The granule cells of the dentate gyrus form the input stage of the hippocampal trisynaptic circuit and their function is strongly influenced by peptidergic systems. GPR54 is highly and discretely expressed in these cells. We have found that activation of GPR54 with kisspeptin-10 causes a rapid and large increase in the amplitude of excitatory synaptic responses in granule cells, without changing membrane properties. The effect was suppressed by the G-protein inhibitor GDP-β-S and the calcium chelator BAPTA, and analysis of miniature EPSCs revealed an increase in mean amplitude but not event frequency, indicating that GPR54 and the mechanisms for enhancing EPSCs are postsynaptic, possibly involving changes in AMPA receptor number or conductance. The kisspeptin-induced synaptic potentiation was abolished by inhibitors of ERK1/2, tyrosine kinase, and CaMKII. RT-PCR experiments showed that KiSS-1 is expressed in the dentate gyrus. KiSS-1 mRNA was significantly increased by seizure activity in rats and when neuronal activity in organotypic hippocampal slice cultures was enhanced by kainate or picrotoxin, while mRNA for GPR54 remained essentially unchanged. These results suggest that kisspeptin may be locally synthesized and act as an autocrine factor. In separate experiments, hippocampal KiSS-1 mRNA in male rats was increased after gonadectomy. In summary, kisspeptin is a novel endogenous factor which is dynamically regulated by neuronal activity and which, in marked distinction from other neuropeptides, increases synaptic transmission in dentate granule cells through signaling cascades possibly linked to the MAP kinase system. This novel peptide system may play a role in cognition and in the pathogenesis of epilepsy.

Introduction

The role of kisspeptin and GPR54 in the brain has been studied almost exclusively in the hypothalamus. However, in situ hybridization showed that some regions of the limbic system, including the amygdala and hippocampus, highly express GPR54 [43], [45], [54]. In both regions, GPR54 expression is concentrated in certain nuclei and neurons. In the amygdala, GPR54 mRNA is mainly found in the cortical nucleus and in the medial nucleus. In the hippocampus, GPR54 density is very high in the granule cell layer of the dentate gyrus (DG) and barely detectable in the pyramidal cells of CA1 and CA3 [45]. This suggests that the kisspeptin–GPR54 system has very selective functions in the brain. We have therefore begun to examine how GPR54 affects the physiology of neurons in the hippocampus and how expression of peptide and receptor is regulated in this structure. We will first present the data from these studies and then discuss some potential roles of this system in hippocampal function.

To put our findings in perspective, it may be useful to summarize briefly some essential features of the dentate gyrus (Fig. 1B). The latter represents the first stage of what is called the hippocampal trisynaptic circuit, the later stages being CA3, CA1, and the subiculum. The principal neuron of the DG is the granule cell which, unlike most other neurons in the brain, is newly generated and turned over throughout life [17]. The cell bodies of granule cells form a compact layer which appears V- or U-shaped in hippocampal cross-sections, and their dendrites extend outwards to form the molecular layer. Underneath the granule cell layer is the hilus or polymorphic layer which contains a heterogeneous population of neurons. The granule cells send their axons in the ‘mossy fiber’ bundle to field CA3 where they make synaptic contacts on giant boutons just above the cell body of the pyramidal cells. However, collaterals of the mossy fiber axons also make numerous contacts on neurons in the hilus, which in turn provide excitatory and inhibitory feedback to granule cells. The main external input to granule cells is the perforant path (PP) which originates in the entorhinal cortex (EC) and makes synapses strictly in the outer two thirds of the molecular layer. The inner third of the molecular layer contains fibers of diverse origins, including the hypothalamus [97], but the most important input comes from the ‘mossy cells’ in the hilus which receive powerful stimulation from collaterals of the granule cell mossy fiber axons and send an excitatory signal back to granule cells [79]. However, unlike the axons of the trisynaptic circuit which mainly stay within a lamina perpendicular to the long axis of the hippocampus, the hilar mossy cell axons extend along the longitudinal (rostral-caudal) hippocampal axis, with synaptic contacts becoming more frequent farther away from the cell body [37], [79]. Thus these cells may integrate information across multiple laminae. Hilar mossy cells, and other hilar neurons, tend to degenerate in temporal lobe epilepsy and there is evidence that this plays a role in the development of seizures [76], [86]. But perhaps the most important change underlying temporal lobe seizures is the sprouting of the granule cell mossy fibers into the inner molecular layer, which may establish a novel excitatory feedback to granule cells [8], [94]. Lastly, granule cells, interneurons, and afferent fibers contain a wide range of neuropeptides, including somatostatin, neuropeptide Y, cholecystokinin, enkephalins, dynorphin, and substance P, and many of them exert control over granule cell excitability, transmitter release, and synaptic plasticity. Perhaps one of the most important factors is brain-derived neurotrophic factor (BDNF) which influences almost every aspect of DG function, including synaptic transmission, synaptic plasticity, neuronal viability, neurogenesis, as well as development of epilepsy and mossy fiber sprouting after seizures [14].

The hippocampus was previously assumed to be a part of a limbic circuitry underlying emotion, but its main role is now widely believed to be to encode declarative and episodic memories and to form spatial maps of the environment. In this cognitive context, the dentate gyrus appears to integrate spatial information delivered from the medial EC and polymodal information about objects from the lateral EC in order to create more specific ‘objects in space’ representations which are then fed into CA3 [31]. Modeling studies indicate that encoding of such representations requires sparse spiking and strong lateral inhibition in the DG [1], [95]. In agreement with this, granule cells exhibit hyperpolarized resting potentials with low rates of spontaneous firing and they require intense synaptic activation to trigger action potentials [89]. However, many authors make the point that the hippocampus is likely to have additional behavioral functions, such as to coordinate olfactory-motor behaviors [96], or to encode sequences of events and to integrate information about spatial positions, motor actions and goals [48]. Gray and McNaughton [28] have developed a theory in which the hippocampus serves to detect and resolve conflicts between competing goals and they specifically propose a role of the hippocampus in anxiety. Moreover, there is growing evidence that changes in hippocampal function are involved in clinical depression [18]. Lastly, there are also suggestions that hippocampal functions are somewhat segregated along the longitudinal axis, with cognitive aspects being more dominant in the rostral (also called dorsal, or septal) part and emotional aspects in the caudal (ventral, temporal) part [9], [55].

Section snippets

Effects on synaptic responses in the dentate gyrus

The high density of GPR54 mRNA in the cell body layer of the dentate gyrus suggested that this receptor is expressed in granule cells and influences their physiology. To test this, we conducted whole-cell recording from DG granule cells. The findings summarized below were previously shown in Arai et al. [6]. AMPA-receptor mediated excitatory postsynaptic currents (EPSCs) were evoked by stimulation in the inner molecular layer under pharmacological isolation. Kisspeptin was applied topically by

KiSS-1 mRNA is expressed in the dentate gyrus, but at lower levels than in the hypothalamus

Brailoiu et al. [15] detected kisspeptin immunoreactivity in several hypothalamic and brainstem regions and also in scattered fibers in the diencephalon, amygdala, and striatum, but not in the cortex or hippocampus. On the other hand, their study also showed that KiSS-1 mRNA can be detected in the cortex and we have likewise found that KiSS-1 is expressed in the dentate gyrus [6]. In more recent tests using semiquantitative RT-PCR, we have found that the hippocampus contains about 50–100 times

Role of the kisspeptin/GPR54 system in the dentate gyrus

The literature on kisspeptin and GPR54 currently suggests that this peptide system may have two separate but system-wide functions, one related to reproduction [78], [82], the other one to regulate cellular processes such as motility and metastasis [34], [50], [57]. However, some reports also indicate that GPR54 may have additional roles. For instance, kisspeptin modulates insulin release from pancreatic islets [32], [84], stimulates aldosterone synthesis in the adrenal gland [56] and acts as

Acknowledgements

This work was supported by a grant from the Whitehall Foundation (2007-05-119) and by funds from the Central Research Committee of the Southern Illinois University School of Medicine.

References (99)

  • C.M. Gall

    Seizure-induced changes in neurotrophin expression: implications for epilepsy

    Exp Neurol

    (1993)
  • J.-A. Girault et al.

    FAK and Pyk2/CAKβ in the nervous system: a link between neuronal activity, plasticity and survival

    Trends Neurosci

    (1999)
  • A. Hori et al.

    Metastin suppresses the motility and growth of CHO cells transfected with its receptor

    Biochem Biophys Res Commun

    (2001)
  • E.M. Hull et al.

    Sexual behavior in male rodents

    Horm Behav

    (2007)
  • M. Illario et al.

    Calcium/calmodulin-dependent protein kinase II binds to Raf-1 and modulates integrin-stimulated ERK activation

    J Biol Chem

    (2003)
  • M.T. Kim et al.

    17beta-Estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3

    Neuroscience

    (2006)
  • G. Krapivinsky et al.

    SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor dependent synaptic AMPA receptor potentiation

    Neuron

    (2004)
  • D.K. Lee et al.

    Discovery of a receptor related to the galanin receptors

    FEBS Lett

    (1999)
  • T.S. Lewis et al.

    Signal transduction through MAP kinase cascades

    Adv Cancer Res

    (1998)
  • T. Masui et al.

    Metastin and its variant forms suppress migration of pancreatic cancer cells

    Biochem Biophys Res Comm

    (2004)
  • A.I. Muir et al.

    AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1

    J Biol Chem

    (2001)
  • J.S. Oh et al.

    Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II

    J Biol Chem

    (2004)
  • E.M. O’Kane et al.

    Increased long-term potentiation in the CA1 region of rat hippocampus via modulation of GTPase signalling or inhibition of Rho kinase

    Neuropharmacology

    (2004)
  • J.M. Parent et al.

    Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat

    Neurosci Lett

    (1998)
  • G.D. Petrovich et al.

    Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems

    Brain Res Brain Res Rev

    (2001)
  • F.R. Poulsen et al.

    Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry

    Neuroscience

    (2004)
  • A.H. Ratzliff et al.

    Mossy cells in epilepsy: rigor mortis or vigor mortis?

    Trends Neurosci

    (2002)
  • J. Roa et al.

    New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function

    Front Neuroendocrinol

    (2008)
  • J.M. Schmitt et al.

    Calcium activation of ERK mediated by calmodulin kinase I

    J Biol Chem

    (2004)
  • A. Tashiro et al.

    Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility

    Mol Cell Neurosci

    (2004)
  • C.H. Vanderwolf

    The hippocampus as an olfacto-motor mechanism: were the classical anatomists right after all?

    Behav Brain Res

    (2001)
  • Z. Xie et al.

    Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6

    Neuron

    (2005)
  • J.J. Zhu et al.

    Ras and Rap control AMPA receptor trafficking during synaptic plasticity

    Cell

    (2002)
  • J.P. Adams et al.

    The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK

    J Neurochem

    (2000)
  • J. Altman et al.

    Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

    J Comp Neurol

    (1965)
  • A.C. Arai et al.

    Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action

    J Pharmacol Exp Ther

    (2002)
  • A.C. Arai et al.

    Cancer metastasis-suppressing peptide metastin upregulates excitatory synaptic transmission in hippocampal dentate granule cells

    J Neurophysiol

    (2005)
  • Arai AC, Orwig N. Factors that regulate KiSS-1 gene expression in the hippocampus. Brain Res, in...
  • M.V. Baratta et al.

    Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate gyrus

    J Neurophysiol

    (2002)
  • J. Bengzon et al.

    Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures

    Proc Natl Acad Sci USA

    (1997)
  • M. Bilban et al.

    Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts

    J Cell Sci

    (2004)
  • G.C. Brailoiu et al.

    KiSS-1 expression and metastin-like immunoreactivity in the rat brain

    J Comp Neurol

    (2005)
  • S. Campbell et al.

    The role of the hippocampus in the pathophysiology of major depression

    J Psychiatry Neurosci

    (2004)
  • J.M. Castellano et al.

    Expression of KiSS-1 in rat ovary: putative local regulator of ovulation?

    Endocrinology

    (2006)
  • D.A. Coulter et al.

    Functional regulation of the dentate gyrus by GABA-mediated inhibition

    Prog Brain Res

    (2007)
  • V. Derkach et al.

    Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

    Proc Natl Acad Sci USA

    (1999)
  • L. Fester et al.

    Proliferation and apoptosis of hippocampal granule cells require local oestrogen synthesis

    J Neurochem

    (2006)
  • C. Gall

    Seizures induce dramatic and distinctly different changes in enkephalin, dynorphin, and CCK immunoreactivities in mouse hippocampal mossy fibers

    J Neurosci

    (1988)
  • J.A. Gray et al.

    The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system

    (2000)
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