Neuropeptide Transmission in Brain Circuits
2012; Cell Press; Volume: 76; Issue: 1 Linguagem: Inglês
10.1016/j.neuron.2012.09.014
ISSN1097-4199
Autores Tópico(s)Neuropeptides and Animal Physiology
ResumoNeuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G protein-coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G protein-coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. Just as there are multiple perceptions for the proverbial blind men as to what an elephant is, there are numerous perspectives one can adopt to view neuropeptide modulation in the CNS. Here, I take the view that neuropeptide modulation in the CNS is inextricably linked with fast amino acid GABA and glutamate signaling. Many other viable perspectives exist and are not mutually exclusive. I have used a few examples of peptide secretion and actions which may be representative of many brain regions not discussed herein; many of the examples used here are from the hypothalamus, the part of the brain where neuropeptides have been most thoroughly studied. Many important neuropeptides are not included in the review. Although the focus here is on neuropeptides, some of the mechanisms of release and many of the mechanisms of response to neuropeptides may generalize to other neuromodulators in the brain, including the catecholamines, serotonin, adenosine, endocannabinoids, and neurotrophic factors. Neuropeptides can exert direct effects on neuronal physiology within seconds to minutes, and can also modulate gene expression over the course of hours to days; the focus here is on the direct neurophysiological actions. The nomenclature of neuropeptides can initially be confusing. Names of CNS neuropeptides often give a historical perspective indicating what the peptide-pioneers initially discovered as the putative function. Since many neuropeptides were discovered in the context of regulation of hormone release, neuropeptide names may bear that functional link. True to its name, somatostatin released into the portal blood supply of the median eminence from nearby hypothalamic neurons can decrease growth hormone secretion from the pituitary gland; on the other hand, the somatostatin-synthesizing neurons in the cortex and hippocampus have no functional relation to hormone regulation. The same is true for thyrotropin-releasing hormone in thalamic neurons, and vasopressin- and gastrin-releasing peptide in circadian clock neurons of the suprachiasmatic nucleus where the neuropeptide names have no bearing on their local function. Despite strong evidence showing substantive functional roles for many neuropeptides, at the cellular level a number of mysteries remain. Even seemingly straightforward questions can be complicated, such as: how far from a neuronal neuropeptide release site does a peptide act? For the amino acid neurotransmitters GABA, glycine, and glutamate, release occurs to a large degree at a presynaptic active zone, the transmitter diffuses a few tens of nanometers, activates receptors on the postsynaptic neuron, and then the transmitter is rapidly degraded or transported intracellularly. Amino acid transmitters act rapidly at ionotropic receptors and at very discrete and spatially adjacent synaptic sites. Neuropeptides, in contrast, may be released from many additional release sites not restricted to the synaptic specialization, raising the question of where they act. For example, in classic work on the frog sympathetic ganglia, a gonadotropin-releasing hormone (GnRH)-like peptide was released by preganglion axons and acted on cells some microns away from the release site (Jan and Jan, 1982Jan L.Y. Jan Y.N. Peptidergic transmission in sympathetic ganglia of the frog.J. Physiol. 1982; 327: 219-246PubMed Google Scholar). Even in the case of nonsynaptic release, a neuropeptide could still act on cells that are postsynaptic to the axon that releases it. For instance, GABAergic neuropeptide Y (NPY) cells of the arcuate nucleus make synaptic contact with other nearby arcuate nucleus neurons that synthesize proopiomelanocortins (POMC); NPY hyperpolarizes the POMC neurons (Cowley et al., 2001Cowley M.A. Smart J.L. Rubinstein M. Cerdán M.G. Diano S. Horvath T.L. Cone R.D. Low M.J. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.Nature. 2001; 411: 480-484Crossref PubMed Scopus (970) Google Scholar), and therefore even though NPY may not be released synaptically, it can still exert an inhibitory effect on the cell postsynaptic to its parent axon. A second possibility that has received considerable attention is that the peptide can diffuse long distances to act far from the release site. Very long distance signaling has been found for a number of neuroactive peptides/proteins. For instance, leptin from adipose tissue, ghrelin from the stomach, and insulin from the pancreas are released a long distance from the brain but act on receptors within the CNS as signals of energy homeostasis. The blood brain barrier may prohibit entrance into the brain for many blood borne peptides; on the other hand, some regions of the brain such as the median eminence/arcuate nucleus may maintain a weak blood brain barrier which permits blood borne signals to enter the brain. Enhanced transport mechanisms may also exist for facilitating movement of some peptides into the brain. Long-distance signaling within the brain has been called volume transmission, and there is a substantial body of literature addressing this (Fuxe et al., 2005Fuxe K. Rivera A. Jacobsen K.X. Höistad M. Leo G. Horvath T.L. Staines W. De la Calle A. Agnati L.F. Dynamics of volume transmission in the brain. Focus on catecholamine and opioid peptide communication and the role of uncoupling protein 2.J. Neural Transm. 2005; 112: 65-76Crossref PubMed Scopus (35) Google Scholar, Fuxe et al., 2007Fuxe K. Dahlström A. Höistad M. Marcellino D. Jansson A. Rivera A. Diaz-Cabiale Z. Jacobsen K. Tinner-Staines B. Hagman B. et al.From the Golgi-Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: wiring and volume transmission.Brain Res. Brain Res. Rev. 2007; 55: 17-54Crossref Scopus (84) Google Scholar; Jansson et al., 2002Jansson A. Descarries L. Cornea-Herbert V. Riad M. Verge D. Bancila M. Agnati L.F. Fuxe K. Transmitter-receptor mismatches in central dopamine, serotonin, and neuropeptide systems. Further evidence for volume transmission.in: Walz W. The Neuronal Environment: Brain Homeostasis in Health and Disease. Humana Press, Totowa, NJ2002: 83-101Google Scholar). Consistent with long distance diffusion, neuropeptide receptors aided by G protein amplification tend to be sensitive to low nanomolar concentrations of peptide; this compares to the substantially less sensitive ionotropic amino acid receptors that respond to micromolar quantities of GABA or glutamate. Furthermore, some peptides have been suggested to maintain a long extracellular half-life (Ludwig and Leng, 2006Ludwig M. Leng G. Dendritic peptide release and peptide-dependent behaviours.Nat. Rev. Neurosci. 2006; 7: 126-136Crossref PubMed Scopus (253) Google Scholar), thereby maintaining activity during the temporal window required for diffusion. In many parts of the brain, the expression patterns of peptide-containing processes and the homologous peptide receptors overlap, consistent with a local action of the neuropeptide. But in a large number of CNS loci, the anatomical expression of a particular peptide and its receptors may be in completely different regions of the brain, as noted in the extensive review of such anatomical mismatches by Herkenham, 1987Herkenham M. Mismatches between neurotransmitter and receptor localizations in brain: observations and implications.Neuroscience. 1987; 23: 1-38Crossref PubMed Google Scholar. This peptide-receptor mismatch could be simply a nonfunctional throwback to some partial preservation of an interaction that was important in the evolutionary past but is no longer relevant. Alternately, for peptides such as oxytocin, there may be massive release due to the simultaneous activation of a majority of oxytocin neurons within the brain; this can raise the extracellular oxytocin in the area of the supraoptic nucleus to a level 100-fold greater than circulating oxytocin (Ludwig and Leng, 2006Ludwig M. Leng G. Dendritic peptide release and peptide-dependent behaviours.Nat. Rev. Neurosci. 2006; 7: 126-136Crossref PubMed Scopus (253) Google Scholar), allowing diffusion of a higher concentration of peptide to activate oxytocin receptors at more distant sites than would be possible with asynchronous firing. Arguing against long distance release and response as a general rule is the fact that a number of neuropeptides, for instance, NPY, dynorphin, or somatostatin, are synthesized and released by many unrelated groups of neurons in different regions of the brain. Any specific role of the peptide relevant to the releasing neuron would be negated if the same peptide from other brain regions was diffusing long distances. Furthermore, peptidases actively break down peptides extracellularly, reducing the effective distance an active peptide may diffuse. Depending on the size, presence of disulfide bonds which increase peptide half-life, amidation, and chemical confirmation of the peptide, peptide half-lives can vary. Administration of a particular peptide or other modulator into a receptor-rich region of the brain lacking in that particular peptide can generate very selective functional responses, suggesting a functional plausibility to volume transmission. However, neuropeptide receptors simply respond to peptide, and even if the response is specific for a particular brain region or circuit, it may be simply a response of selective circuit activation or inhibition that may not normally occur. A more convincing strategy to show that long distance neuropeptide diffusion may play a functional role would be the use of a receptor antagonist in a region lacking specific peptidergic inputs to show the opposite effect of peptide injection; but even the receptor antagonist strategy can be complicated, as some receptor antagonists may act as inverse agonists, reducing a constitutively active receptor to a level below a normal partially-active state. For the majority of axons in the CNS that release neuropeptides, I favor a third local diffusion hypothesis- that neuropeptides released by most neurons act locally on cells near the release site, with a distance of action of a few microns. Thus, a peptide’s action would be on its synaptic partners (even if the peptide is not released at the presynaptic specialization) and on immediately adjacent cells. In part this perspective is based on the low frequency of dense core vesicles in most CNS axons and the hours it would take to replenish released peptides from sites of synthesis in the cell body, making it difficult to achieve a substantial extracellular concentration of neuropeptide needed for a long-distance effect. In this context, the relatively slow replenishment of neuropeptide modulators may differ from catecholamine neuromodulators that can be synthesized rapidly within axon terminals to support ongoing release. Furthermore, as determined with ultrastructural analysis, a complex system of astrocytic processes surrounds many axodendritic synaptic complexes and tends to attenuate long-distance transmitter diffusion from many release sites (Figure 1; Peters et al., 1991Peters A. Palay S.L. Webster H. The Fine Structure of the Nervous System. Oxford University Press, Oxford1991Google Scholar), thereby impeding actions of peptides at far-away targets, and maintaining a higher local extracellular concentration of the peptide. Peters et al. credit Ramon y Cajal with favoring the concept that a central function for glia was isolation of neuronal microdomains. That peptides released by most neurons may act within a few microns of the release site does not negate the fact that some peptides can be released in large quantities and can act at longer distances. This may be the exception rather than the rule. For instance, considering the multiple subtypes of highly specialized NPY or somatostatin interneurons in the hippocampus or cortex, coupled with the multiple peptide responses reported in nearby cells and the highly specialized functions of different nearby interneurons, often with restricted functional microdomains (Freund and Buzsáki, 1996Freund T.F. Buzsáki G. Interneurons of the hippocampus.Hippocampus. 1996; 6: 347-470Crossref PubMed Google Scholar; Bacci et al., 2002Bacci A. Huguenard J.R. Prince D.A. Differential modulation of synaptic transmission by neuropeptide Y in rat neocortical neurons.Proc. Natl. Acad. Sci. USA. 2002; 99: 17125-17130Crossref PubMed Scopus (43) Google Scholar; Klausberger et al., 2003Klausberger T. Magill P.J. Márton L.F. Roberts J.D. Cobden P.M. Buzsáki G. Somogyi P. Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo.Nature. 2003; 421: 844-848Crossref PubMed Scopus (546) Google Scholar), it seems most likely that released peptides here act primarily on nearby receptive partners. Consistent with the local diffusion perspective are findings related to peptides such as pigment dispersing factor (PDF) which plays a key role in regulating circadian rhythms of invertebrates (Im and Taghert, 2010Im S.H. Taghert P.H. PDF receptor expression reveals direct interactions between circadian oscillators in Drosophila.J. Comp. Neurol. 2010; 518: 1925-1945Crossref PubMed Scopus (37) Google Scholar; Zhang et al., 2010Zhang L. Chung B.Y. Lear B.C. Kilman V.L. Liu Y. Mahesh G. Meissner R.A. Hardin P.E. Allada R. DN1(p) circadian neurons coordinate acute light and PDF inputs to produce robust daily behavior in Drosophila.Curr. Biol. 2010; 20: 591-599Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Although cells that release PDF project to several regions of the Drosophila brain, the response of the releasing cells to PDF appears to be critical for some aspects of circadian function. Secreted PDF acts on PDF autoreceptors expressed by the releasing lateral-ventral pacemaker neurons to regulate the time of day during which behavioral activity occurs (Choi et al., 2012Choi C. Cao G. Tanenhaus A.K. McCarthy E. Jung M. Schleyer W. Shang Y. Rosbash M. Yin J.C.P. Nitabach M.N. Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in Drosophila.Cell Reports. 2012; 2: 332-344Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar; Taghert and Nitabach, 2012Taghert P.H. Nitabach M.N. Peptide neuromodulation in invertebrate model systems.Neuron. 2012; 71 (this issue): 82-97Abstract Full Text Full Text PDF Scopus (9) Google Scholar, this issue of Neuron). Most neuropeptides act by binding to a seven-transmembrane domain G protein-coupled receptor (GPCR). Many hundreds of these receptors have been identified and their normal ligand is known; the ligands for a number of orphan GPCRs have not yet been identified (see Civelli, 2012Civelli O. Orphan GPCRs and neuromodulation.Neuron. 2012; 76 (this issue): 12-21Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, this issue of Neuron). Binding to the GPCR induces a conformational change in the receptor, leading to activation of intracellular G proteins. Many G proteins exist in an inactive heterotrimeric form consisting of Gα, Gβ, and Gγ. Activation results in an exchange of GDP for GTP at the G protein’s α subunit and the dissociation of the G proteins from the GPCR. Peptide signaling is then amplified by the induction of multiple intracellular signaling pathways that may involve adenylyl cyclase, cAMP, MAPK/ERK, PKA, and phosphorylation of a number of target proteins. Monomeric G proteins may also play a role in modulating some ion channels and actions of peptides (Murray and O’Connor, 2004Murray H.J. O’Connor J.J. A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro.Brain Res. 2004; 1000: 85-91Crossref PubMed Scopus (11) Google Scholar; Vögler et al., 2008Vögler O. Barceló J.M. Ribas C. Escribá P.V. Membrane interactions of G proteins and other related proteins.Biochim. 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The actions of neuropeptides on GPCRs can also be modulated at the receptor or effector level; for instance, members of the RGS (regulator of G protein signaling) family of proteins can accelerate activation or deactivation of G proteins and may alter receptor-effector coupling (Chuang et al., 1998Chuang H.H. Yu M. Jan Y.N. Jan L.Y. Evidence that the nucleotide exchange and hydrolysis cycle of G proteins causes acute desensitization of G-protein gated inward rectifier K+ channels.Proc. Natl. Acad. Sci. USA. 1998; 95: 11727-11732Crossref PubMed Scopus (96) Google Scholar; Doupnik et al., 2004Doupnik C.A. Jaén C. Zhang Q. Measuring the modulatory effects of RGS proteins on GIRK channels.Methods Enzymol. 2004; 389: 131-154Crossref PubMed Scopus (24) Google Scholar; Labouèbe et al., 2007Labouèbe G. Lomazzi M. Cruz H.G. Creton C. Luján R. Li M. Yanagawa Y. Obata K. Watanabe M. 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Neuroendocrinol. 2012; 33: 45-66Crossref PubMed Scopus (6) Google Scholar). Peptide receptors are found heterogeneously distributed throughout the brain, and can be expressed on cell bodies, dendrites, and axon terminals. Some peptides, for instance NPY, activate multiple different receptors expressed by target neurons, whereas others appear to act primarily on a single receptor, for instance kisspeptin acts primarily on GPR54. Our understanding of peptide receptor subcellular localization has lagged behind that of amino acid receptor localization, in part due to questionable specificity of some peptide receptor antisera. Perhaps the clearest picture that emerges of a class of neuronal GPCRs is for metabotropic glutamate receptors (mGluRs). These function similarly to neuropeptide GPCRs but are activated by glutamate and can act in an excitatory or inhibitory manner. Subcellular localization of mGluRs may provide some insight into the potential localization of neuropeptide GPCRs. Eight different mGluRs have been identified and, interestingly, are expressed in different regions of different neurons. mGluR7, for instance, is often found at the presynaptic active zone (Schoepp, 2001Schoepp D.D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system.J. Pharmacol. Exp. Ther. 2001; 299: 12-20PubMed Google Scholar) and mGluR4, -7α, and -8α are found on the presynaptic active zone of inhibitory axons, and only those innervating other GABA interneurons but not those innervating excitatory pyramidal cells (Kogo et al., 2004Kogo N. Dalezios Y. Capogna M. Ferraguti F. Shigemoto R. Somogyi P. Depression of GABAergic input to identified hippocampal neurons by group III metabotropic glutamate receptors in the rat.Eur. J. Neurosci. 2004; 19: 2727-2740Crossref PubMed Scopus (33) Google Scholar). mGluR1α is found on the postsynaptic membrane at the periphery of the synapse active zone (Baude et al., 1993Baude A. Nusser Z. Roberts J.D. Mulvihill E. McIlhinney R.A. Somogyi P. The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction.Neuron. 1993; 11: 771-787Abstract Full Text PDF PubMed Scopus (615) Google Scholar); other mGluRs tend to be either pre- or postsynaptic, depending on the expressing neuron and mGluR subtype (Bradley et al., 1996Bradley S.R. Levey A.I. Hersch S.M. Conn P.J. Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies.J. Neurosci. 1996; 16: 2044-2056Crossref PubMed Google Scholar). Future experiments on the ultrastructural localization of neuropeptide receptors may show similar sites of expression at specific regions of the plasma membrane. The classic view that neuropeptide-containing neurons represented an unusual type of neuron is giving way to the perspective that many, perhaps most neurons in the brain, probably contain some neuropeptide(s) or other neuromodulator in addition to fast-acting amino acid neurotransmitters. In an examination of individual sections containing synaptic boutons with electron microscopy, with the boutons fixed to preserve the dense core of vesicles, some boutons appeared to contain only clear vesicles, others contained clear and DCVs. However, serial ultrathin section reconstruction of GABA-immunogold-labeled presynaptic boutons from the paraventricular nucleus demonstrated that every bouton contained at least a few dense core vesicles, suggesting that in addition to a fast amino acid transmitter, most if not all GABAergic axons here also contained some neuromodulator (Decavel and van den Pol, 1990Decavel C. van den Pol A.N. GABA: a dominant neurotransmitter in the hypothalamus.J. Comp. Neurol. 1990; 302: 1019-1037Crossref PubMed Scopus (315) Google Scholar). Release and actions of these neuromodulators remains to be demonstrated. Furthermore, because the axons studied contained GABA which is not found in magnocellular neurons, the profiles could not arise from the local oxytocin or vasopressin neurosecretory cells. Similarly, presynaptic boutons showing no immunogold GABA labeling, many of which were probably glutamatergic, also showed a similar frequency of DCVs in boutons, interspersed with small clear vesicles. A complication to the detection of DCVs with electron microscopy is that the dense core can be lost by suboptimal fixation pH, duration, chemistry, and osmotic pressure (Morris and Cannata, 1973Morris J.F. Cannata M.A. Ultrastructural preservation of the dense core of posterior pituitary neurosecretory granules and its implications for hormone release.J. Endocrinol. 1973; 57: 517-529Crossref PubMed Google Scholar), complicating detection in some studies and biasing results toward a false-negative lack of detectable DCVs. A related question is whether all peptidergic axons also contain a fast amino acid transmitter. Most evidence, including that based on immunocytochemistry, calcium digital imaging, and electrophysiology supports the perspective that the great majority of peptidergic cells also employ fast amino acid transmitters (van den Pol, 1991van den Pol A.N. Glutamate and aspartate immunoreactivity in hypothalamic presynaptic axons.J. Neurosci. 1991; 11: 2087-2101PubMed Google Scholar, van den Pol, 2003van den Pol A.N. Weighing the role of hypothalamic feeding neurotransmitters.Neuron. 2003; 40: 1059-1061Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar; van den Pol et al., 1990van den Pol A.N. Wuarin J.P. Dudek F.E. 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For instance, in the hippocampus, a region with a rich history in the study of fast GABA and glutamate transmission, a plethora of neuropeptides are synthesized, particularly by GABAergic inhibitory interneurons, including neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, dynorphin, enkephalin, neurokinin B, and substance P (Acsády et al., 1996Acsády L. Arabadzisz D. Freund T.F. Correlated morphological and neurochemical features identify different subsets of vasoactive intestinal polypeptide-immunoreactive interneurons in rat hippocampus.Neuroscience. 1996; 73: 299-315Crossref PubMed Scopus (97) Google Scholar, Acsády et al., 2000Acsády L. Katona I. Martínez-Guijarro F.J. Buzsáki G. Freund T.F. Unusual target selectivity of perisomatic inhibitory cells in the hilar region of the rat hippocampus.J. Neurosci. 2000; 20: 6907-6919PubMed Google Scholar; Billova et al., 2007Billova S. Galanopoulou A.S. Seidah N.G. Qiu X. Kumar U. 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Brain Res. 1997; 115: 423-429Crossref PubMed Scopus (22) Google Scholar; Freund and Buzsáki, 1996Freund T.F. Buzsáki G. Interneurons of the hippocampus.Hippocampus. 1996; 6: 347-470Crossref PubMed Google Scholar). Hippocampal pyramidal cells, often used as a primary model for the study of glutamatergic neurons, are reported to express peptides, for instance cholecystokinin (Wyeth et al., 2012Wyeth M.S. Zhang N. Houser C.R. Increased cholecystokinin labeling in the hippocampus of a mouse model of epilepsy maps to spines and glutamatergic terminals.Neuroscience. 2012; 202: 371-383Crossref PubMed Scopus (3) Google Scholar), particularly in models of brain disease such as epilepsy. From an evolutionary perspective, peptide synthesis in invertebrates may give us clues as to the parallel in vertebrates. In Aplysia, every identified motorneuron was found to contain one or more of a number of different peptide modulators (Church and Lloyd, 1991Church P.J. Lloyd P.E. Expression of diverse neuropeptide cotransmitters by identified motor neurons in Aplysia.J. Neurosci. 1991; 11: 618-625PubMed Google Scholar). Scientists have a keen insight into the temporal sequence and many of the molecules involved in the release of fast neurotransmitters at presynaptic specializa
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