ReviewThe role of kisspeptin and GPR54 in the hippocampus
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.
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