- Email: [email protected]
VIP neurons in the cerebral cortex
TiPS -June 2990 Rot. II)
Pierre J. Magistretti V~P-~onfai~~ugcelfs in fke ~eocorfe~ are ~nfrins~cneurons of the bipolar type, wkick release VlP f~zrorfg~r ~nec~lunismsfkaf involve CaZ+ and lipoxyge~use mefabolifes. VlP receptors are coupled to CAMP-generatingsystems that are n~lp~~~edby various ~eurotra~smi~ferssuck us noradre~a~~~e,kista~ine and GABA. Pierre Magistretti reviews the evidence fkaf VIP neurons play an important role in the local regulation of metabolism in the cerebral cortex by stimulafing glycogenolysis and alfering cortical blood flow, Vasoactive intestinal peptide (VIP) is a basic peptide of 28 amino acid residues, amidated at the carboxyl terminus (Fig. I), which was originally identified in the gastrointestinal tract by Said and Mu&. The gene encoding the precursor of human VIP consists of seven exons spanning approximately 9 kb (Ref. 2). Exon four encodes VIP while peptide histidinemethionine (PHM), a peptide sharing sequence homolo~es and activities with VIP, is encoded by exon 5 (Ref. 2). Like various other peptides of gas~intestin~ or endocrine origin, VIP is also present in the nervous system. This article focuses on the properties of VIP as a neurotransmitter of the cerebral cortex and their pharmacological relevance (see Ref. 3 for a more general review). Localization and co-localization In rodent brain, the highest concentrations of VIP are found in certain h~o~al~ic nuclei and in the cerebral cortex (see Ref. 4). in the cortex VIP is contained in a homogeneous population of radially oriented, bipolar interneunms. Because their dendritic arborization diverges only slightly from the main axis of the celle, these intracortical neurons exert very Iocalized input-output functions within radial :ortical ‘columns‘ (Fig. 2). The majority of VIP cortiCal neurons form symmetric synapse@ - a feature generally taken to indicate an inhibitory nature. Such VIP-immunoreactive synapses generally occur on dendritic shafts. In cortical bipolar
neurons, VIP is co-localized with GAPA (3 30% co-localization) and with acetylcholine (> 80% CO1ocalization)s. Thus, physiological and pharmacological interactions between these three neurotransmitters are likely to exist at the pre- and postsynaptic levels. Release Depolarizing stimuli release VIP from neocortical slices in a Ca2+-dependent manner. K+evoked release of VIP is insensitive to Ca2+ channel blockers such as dihydrop~dines, ctlconotoxin and Cd2+, but is inhibited by Nia+, ruling out the involvement of the voltage-sensitive L- and N-type Caa* channel@. By contrast, CNS amine release appears to involve the opening of Ntype channels. Wheth~ this reflects a general difference between amine and peptide release from CNS neurons, or is a peculiarity of the UP-containing intracortical system remains to be determined. Releaseof VIP can also be evoked by 4-~inopy~dine~ a K+ channel blocker. Such release is transsynaptic in nature, since it is largely tetrodotoxin-sensitive; furthermore it involves the formation cf arachidonic acid metabelites of the lipoxygenase pathway since it is decreased by the lipoxygenase inhibitors nordihydroguaiaretic acid, caffeic acid and 5,8,11.,14-eicosatetraynoicacid7. This observation suggests that Caminopyridine evokes the release of one or more cortical neurotransmitters which in turn modulate(s) VIP release via the arachidonic acid cascade. Such modulations of neurotransmitter release by arachidonic acid metabolites of the lipoxygenase pathway have been demonstrated in elegant exper-
iments on identified Aplysia neuron@. In viva studies in cat neocortex indicate that in fact VIP release is under the control of various neurotransmitter systems. Thus GABA, opioids (via y-opioid receptors) and noradrenaline (via fw2-adrenoceptors) inhibit, while cholinoceptor agonists and glutamate stimulate the release of VIP (Ref. 9). Receptors and second messengers Saturable and specific binding of m%IabeIled VIP to cerebral cortical membranes has been demonstrated in several rodent species {see Ref. IO). In the rat neocortex, the highest density of VIP binding sites occurs in layers I, II, IV and VI, as revealed by autoradiographyll; other CNS areas rich in VIP recognition sites are the olfactory bulb, dentate gyrus, subiculum, various thalamic and h~oth~~ic nuclei, locus coeruleus and the pineal gland”. The subependymal layer at the level of all ventricles, the area postrema, subfornical and subcommissural organs are also very rich in binding sites, indicating a possible role for VIP in cerebrospinal fluid homeostasis and blood-brain barrier permeability. The main second messenger pathway activated by VIP receptor occupation is the G protein-adenylyf. ~clase-me~ated increase in CAMP (see Ref. 12). VIP-stimulated CAMP formation has been shown in various species and appears to be subject to modulation by several other cortical neurotransmitters (see below). Studies in purified preparations have revealed that astroeytes and intraparenchymal cerebral cortical microvessels may be the target cells in which CAMP increases are elicited by VIP released from the iutracortical VIP neuronal system (see Ref. 4). The presence of VIPpositive synapses, which are all of the symmetric (i.e. inhibitory) type and which are mainly on dendritic shaft@, demonstrates that neurons and in particular pyramidal cells are also the targets of UP-containing bipolar neurons (Fig. 3). Role in cortical energy me~balism One of the first cellular actions of VIP to be detected was the
TiPS - @2e 1990 fVol. 221
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of CAMP formationI*. While this is an important step in the identification of functional receptors and a useful index for the analysis of potential neurotransmitter (see interactions below), information as to the physiological role(s) of VIP neurons in cerebral cortical circuitry requires (as for any neurotransmitter) the demonstration of cellular actions downstream of second messenger formation. In this context it was instructive to demonstrate that VIP stimulates glycogenolysis in mouse cerebral cortical slices13. Increases in CAMP, by releasing the catalytic subunit of CAMP-dependent protein kinase, trigger various phosphorylation cascades, one of which leads to the conversion of phospho~~ase b to phospho~lase II, a form of the enzyme that is very active in the release of glucose l-phosphate from glycogen (see Box). VIP stimulates cortical glycogenolysis with an ECso of 25 nM; only peptides that share significant sequence homologies with VIP such as peptide histidin&soleucine (PHI) and secretin (13 and nine identical amino acids residues, respectively) exert a similar effect, albeit with lower potencies (EC&s 300 nM and 500 nM, respectively). Human growth hormone-releasing factor (GRF) which, like secretin, shares nine amino acid residues with VIP is inactive; however, only four of these residues are common to the GRF and secretin sequences. This points to a possible role in the activity for the five amino acid positions that are identical in secretin and VIP but not in GRF (Fig. 1). In this context, it will be interesting to examine the effect on cortical glycogen metabolism of helodermin - a peptide with a
29
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high degree of homology with VIP (Fig. I), isolated from the venom of the lizard Gila monste+ The peptide fragments iIP6zs, VIl’1&2s and VIP21-2s do not promote glycogenolysis; nor do other neurotransmitters present in the cerebral cortex, such as GABA,
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glutamate, acetylcholine, somatostatin, cholecystokinin, substance I’, CRF, [Metlenkephalin and [teu]enkephalin*3. The lack of effect of neurotransmitters such as GABA and glutamate is of particular relevance; in contrast to VIP, these neurotransmitters affect
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’
fig. 2. C~umnar o@~iza~on of VIP-~ntaini~ neurons, and the anafomicaf ~bstrafe for the synergistic effecf of ~mu~n~us acti~~on of noradrene~ic cortical afferents and a group of VIP-containing neurons. Such en arrangement would a/tow for the esfablishment of femporary columnar ‘hot spots’ (white cylinder). VIP, VIP-cxx’ttaining bipolar cell; NA, noradrenergic afferent; Pyr. pyramidal cell furnishing major efferent WM. projections; SA, specific afferent (from the thalamus or from otk corticalregions); subcotiicaf white matter. Cortical layers denoted by reman numerals. (Taken, with permission, from Ref. 4.)
TiPS -June 1990 {Vol. 221 1
tfdamo-cortical fibre
F& 3. Anatomtcatorganization and putative targets of the noradrenatifle- and VIPcontainingneumnst circuits in rat cerebral cottex. Left: noradmnergicfibres originatein locus cue~h?us and pqkct to cerebral cortex where they adopt horizontal trajectory parallel m piat surface. Right:VIP neurons are intrinsic to the cerebral cortex and are orientatedvsrticafiy~~~i~ to pial surface. Astrocytes {A&}, tntr~re~~ai b&cd vessels and neurons such as certain pyr~~at ceit.5 (Pyr) are potenttat target c&/e for VIP neumns. Roman numerals indicate cvrtical layers. VIP neumns can be act&ted by specific afferents (e.g. thalanmcoriical fibres). WM. white matter; St, primary somatosensory cortex. (Taken, with permission, from Ref. 4.)
neuronal excitability profoundly. rapidly and in a rapidly reversible manner by altering selective ion conductances13. Thus VIP-stimulated glycogenolysis is a primary event and is not secondary to energy-demanding changes in neuronal firing rate. Their morphological characteristics (Figs 2 and 3) mean that VIP-containing neurons in the neocortex are ideally positioned to regulate the availabili~ of energy substrates released from glycogen locally, within cortical columns (Fig. 2). More than 90% of VIP-positive cells in the neocortex are bipolar neurons - a cell type ideally suited, because their dendrites span sever21 laminae, to receive specific inputs carried by corticocortical or subcortical afferents; this implies that VIP neurons can translate inputs to a given cortical domain into a local metabolic message, thus contibuting to the metabolic homeostasis of activated cortical areas (see Box and Figs 2 and 3). Noradrenaline, 5-HT and histamine also exert a glycogenolytic action in cerebral cortical slices (see Ref. 15). The morphology of the neuronal circuits that contain these monoamines is strikingly
different from that of VIP intracortical neurons: the axons containing monoamines diffusely innervate the neocortex from subcortically localized perikaryaib. For axons example, noradrenergic originate in the locus coeruleus in the brainstem and enter the neocortex rostrally, adopting a tangential trajectory that spans the entire cortical mantle (Fig. 3). These characteristics allow the noradrenergic system to modulate the availability of energy substrates globally and simultaneously across functionally distinct cortical area@ (Figs 2 and 3). Indeed, it is known that unexpected, nonnoxious sensory stimuli activate the locus coeruleus, increasing the ‘noradrenergic tone’ of the neocortexr6; under these conditions, noradrenaline-induced glysogenolysis would become operative. At the cellular level, VIP- and noradren~ine-induced glycogenolysis has been demonstrated in primary cultures of astrocytes*7, the cell type in which glycogen is predominantly stored in the brain (see Box). Interestingly, the ECso for the effect of noradrenaline, which is mediated by B-adrenoceptors, is 100 times lower in
astrocyte cuhures than in cortical slices {S no vs 500 n&x), while that of VIP is of the same order in the two preparations (5 nM in astrocytes and 25 IIM in slices). The lower ECss for noradrenaline in nrltures is probably due to the absence of significant reuptake, and may reflect its actual potency more accurately. The demonstration of neurotransmitter-mediated ~y~ogenolysis in astrocytes in vitro, if representative of interactions occurring in vim, further supports the notion that neurons and glial cells interact in a functionally coordinated manner, in this case to maintain energy metabolism homeostasis. A role of VIP neurons in cortical energy metabolism is further stressed by the presence of VIPstimulated adenylyl cyclase in microvessel intraparenchymal preparations*8 and by the demonstration of functional VIP receptors on pial vessels that mediate an indometacin-sensitive vasodilationlg. It is, however, likely that these receptors are activated by VIP released from fibres in the walls of pial vessels rather than from the intracortical neurons. Thr functional consequences of the increases in CAMP elicited by VIP in ~~p~n~h~~ cortical microvessels remain to be determined; however, activation of the noradrenergic coeruleo-cortical projection produces changes in blood flow and vascular perand it is possible that meability VIP has similar effects. In this context, the demonstration of an increase in Zdeoxyglucose uptake evoked by VIP application to rat anterior cingulate cortex is of great interest*l. Interactions with other cortical neurotransmitters VIP and noradrenaline have synergistic effects on CAMP production in mouse cerebral cortical slicesz2: in addition to increasing CAMP levels through j3-adrenoceptors, noradrenaline acting at ryl-adrenoceptors markedly potentiates the increases in cAMP elicited by VIP (Ref. 22). This potentiation is inhibited by indometacin and mimicked by PCFacu, strongly suggesting the involvement of prostaglandin formation as a result of r+adrenoceptor activationzs. In functional terms these results indicate that the simul-
TiPS - june 1990 [Vol. 111 taneous release of VIP and noradrenaline within a discrete cortical domain, defined by the intersection of the tangential noradrenergic projection and a group of VIPcontaining intracortical neurons activated by specific afferents, may generate a ‘cortical hot spot’ where drastic increases in CAMP levels would occur (Fig. 2). A correlate to these biochemical observations is the demonstration by Siggins and colleagues that VIP and noradrenaline interact synergistically to depress the spontaneous firing rate of cortical neurons; some of these neurons can be identified as pyramidal cells by antidromic stimulation of the pyramidal tractz4 (Figs 2 and 3). Of the other amines contained in extrathalamic cortical afferent36, histamine, but neither 5-I-IT nor acetylcholine, potentiates the increases in CAMP elicited by VIP through an indometacin-sensitive mechanism25. Activation of GABAB receptors by baclofen also
253 potentiates the effects of VIP on CAMP levels via a Cl--sensitive and indometacin-resistant mechanism*s. Since approximately 30% of VIP-positive neurons also contain GABA (Ref. 5), this observation provides a new example of interactions between co-localized neurotransmitters. The production of CAMP elicited by VIP is modulated by steroid hormones in various areas of the rat brain. Adrenalectomy enhances in a dexamethasonereversible manner VIP-stimulated CAMP formation in the amygdala, septum and hippocampusz6. Furthermore, the potentiation exerted by GABAB receptor agonists on the increases in CAMP elicited by VIP in the neocortex is inhibited by chronic corticosterone treatment27. This effect may be mediated by increased synthesis of lipocortin - a negative modulator of phospholipase AZ. While no modulation by acetylcholine on VIP function has yet been demonstrated in the cortex, choline
Glycogen metabolism, VIP neurons and activation-induced glycolysis Glycogen is the single largest energy reserve of the brain. It is predominantly localized in astrocytes, but has also been identified in choroid plexus and ependymal epithelia, in pericytes and in certain large neurons. At the ultrastructural level, glycogen appears as electron-dense isodiametic (10-30 nm) cytoplasmic j3-particles. Glycogen turnover in nervous tissue is very rapid and the enzymes for synthesis and degradation, i.e. phosphorylase and synthase, have been extensively characterized. The activity of these enzymes is regulated by phosphorylation cascades under the control of intracellular second messengers such as CAMP and Ca2+ (for review see Ref. 1). Evidence has accumulated in recent years that challenges the accepted view of the direct coupling between oxidative phosphorylation and increased neuronal activity. Experiments in humans using positron emission tomography indicate that during sensory stimulation the local increase in cerebral blood flow and in glucose uptake is not matched by increased oxygen consumption 2.3.This implies that the increased metabolic needs that occur in an activated cortical region are met by glycolysis, i.e. by the conversion of glucose into lactate, rather than by oxidative glucose metabolism, despite the fact that the latter pathway produces approximately fifteen times more ATP per glucose molecule. Studies in rats indicate that in fact lactate production increases in the somatosensory cortex following forepaw stimulationa. These observations shed some light on the possible role -of glycogen in cortical energy metabolism: glycogen, mobilized locallv bv VIP released from bipolar cells activated by incoming activity may pro6de an immediate sdurce of glucose for -glycolysi< Glycogen stores would in turn be replenished during the increase in both glucose uptake and cerebral blood flow that accompanies the activation of a functionally defined cortical region. References 1 2 3 4
Magistretti, P. J. (1988) DiubeteMetab. 14,237-246 Fox, P. and Raichle, M. (1986) Proc. Nat!Acad. S:i. USA 83, 1140-1144 Fox, P., Raichle, M., Mintum, M. and Dence, C. (1988) Science 241,462-464 Hossmann, K-A. and Linn, F. (1987) J, Cereb. Blood Flow Metnb. 7, S297
acetyltransferase activity and acetylcholine synthesis are increased by VIP in rat hippocampus2s. In spinal cord cultures containing neurons and glial cells, VIP at subnanomolar concentrations prevents the neurr nal loss that occurs when spontaneous electrical activity has been blocked by tetrodotoxinzg. This effect is mediated through an interaction of VIP with non-neuronal cells, most likely astroglia, since it could be observed in mixed cultures (containing both neuronal and non-neuronal cells) and was absent in purely neuronal cultures2g. Such neurotrophic action of VIP may have pharmacological implications. VIP and sleep mechanisms The intraventricular injection of VIP produces a marked increase in rapid eye movement (REM) sleep and a decrease in the waking time in rats30. Furthermore in rats in which sleep duration is considerably decreased as a result of ptreatment, chlorophenylalanine VIP restores both slow-wave sleep and REM sleep to almost normal levels30. A similar hypnogenic effect of the peptide has been observed in cats, a species in which the capacity of VIP to restore REM sleep is blocked by the a*-adrenoceptor agonist clonidine and augmented by the cholinoceptor antagonist atropineal. Whether such effects relate to the physiological function of the VIP intracortical system remains to be determined; however, the presence of VIP receptors has been demonstrated in various regions of the CNS involved in sleep modulation, such as the locus coeruleusl’. q
cl
q
The morphological characteristics of the VIP-containing intracortical system imply that the cellular actions of VIP are exerted with high spatial resolution. These actions appear to converge into a metabolic function, as is indicated by the effects of VIP on energy metabolism and blood flow. cAMI’ and prostanoids are two effector pathways that translate (and amplify in the case of prostanoids) VIP receptor occupation into a cellular effect. Arachidonic acid
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metabolites in particular may play a crucial role in modulating VIP circuits, since prostaglandins enhance a post-synaptic effect of VIP, i.e. cAMP formation, and lipoxygenase metabolites are involved in VIP release from presynaptic sites. The development of potent antagonists and nonpeptide analogues of VIP that can cross the blood-brain barrier will make an important con~bution to understanding of the physiology of the VIP intracortical neuronal system, and of the potential for pharmacoIogica1 intervention in cortical energy metabolism under conditions such as ischaernia or aging. Acknowledgements Research in P@l’s laboratory is supported by the Swiss National Science Foundation (Grant No. 31-26427.89). The author is gratefuI to MS M. Emch for expert secretarial help.
1 Said. S. I. and Mutt, V. (1970) Sciexe 169.1217-1218 2 Linder, S. et at. (1987) Proc. Nafi Acad. Sci. USA 84,6OS-609 3 Said, S. I. and Mutt, V., eds (1988) Ann. NY Acad. Sci. 527,1-691 4 Magistretti, P. J. and Morrison, J. H. (1988) Neuroscience 24.367-378 5 Peters, A. and Harriman, K. M. (1988) J. Camp. Neural. 267,409-432 6 Martin, J-L. and Magi&ret& P. J. (1989) Neuro5~eace 30,423-X+1 7 Martin, J-L. and Magistretti, P. J. (1989) J. Neurosci. 9, 253&2542 8 PiomeUi, D. et ol. (1987) Nature 328, 38-%3 9 Wang, J. Y., Yaksh, ‘I’. L., Harty, G. J. and Go, V. L. W. (19%) Am. J, Pkysiol. 250, RlOPRlll 10 Staun-Olsen, P. et at. (1982) [, Neuro&em. 39,1242-1251 11 Martin, J-L., Die& M. M., Hof, P. R., Palacias, J. M. and Magistretti, P. J. (1987) Neuroscience 23, 539-565 12 Said, S. I., ed. (1982) Advances in Peptide Hormone Research Series, pp. 1-512, Raven Press 13 Magistretti, P. J., Morrison, J. H., Shoemaker, W. J., Sapin, V. and Bloom, F. E. (1981) Proc. Nat1Acad. Sci. USA 78, 6535-6539 14 Robberecht, P. et al. (1984) FEBS Lett. 166.277-282 15 Magistretti, P. J. (1988) Diabete Metab. 14,237-246 16 Foote, S. L. and Morrison, J. H. (1987) Ann. Rev. hieurosci. l&67-95 17 Magistretti, P. J., Manthorpe, M., Bloom, F. E. and Varon, S. (1983) Regul. Pept. 6, 71-80 18 Huang. M. and Rorstad, 0. P. (1984) J. Neurockcm. 43, 849-856 19 Wei, E. I’., Kontos, H. A. and Said, 5.1. (1980) Am. 1. Pkysiol. 239, H765-H768 20 Raichle, M. E., Nartman, B. K., Eichling,
J. 0. and Sharpe, L. G. (1975)Proc.Nat1 Acad. Sci. USA 72, 3726-3730 21 McCulloch, J. and Kelly, P.A.T. (1983) Nafirre 304,438-440 22 Magistretti, I’. J. and Schorderet, M. (1984) Nature 308,280-282 N., Schorderet, M. and 23 Schaad, Magistretti, P. J. (1987) Nature 328, 637-640 24 Ferron, A., Siggins, G. R. and Bloom, F. E. (1985)Proc.Nafl Acad. Sci. USA82, 8810-8812 25 Schaad, N. C., Schorderet, M, and Magis~tti, P. J. f1989) f. ~ei~roc~zesr. 53, 1941-1951 26 Harrelson, A. L., Rostene, W. and
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28 29
30 31
McEwen, 8. S. (1987) J. Nerrrockem. 48, 1648-1655 Duman, R. S., Karbon, E. W., Harrington, C. and Enna, S. J. (1986) 1. Netirocke~. 47,800-810 Lapchak, P. A. and Collier, 3. (1988) f. Neurockem. 50,58-64 Brenneman, D. E., N&e, E. A., Foster, G. A., d’Autremont, S. W. and Westbrook, G. L. (1987) 1. Cell Biol. 104, 1603-1610 Riou, F., Cespuglio, R. and Jouvet, M. (1982) Nearo~e~f~~es2, 26%277 Jimenez-Anguiano, A., Prosp&oGarcia, 0. and Trucker-Colin, R. (1989) Sot. Neurosci. Abstr. 15, 242
xcitat~~ a ino acid receptors, second messengers and iegulation of intra~eii~lar a*+ in mammalianW Mark L. Mayer and Richard J. Miller As we have learnt from earZier arficles in our series on the pharmacology of excitatory amino acids, neurons andglia express several subtypes of excitatory amino acid receptor, the activation of which increases intracellular free calcium ion concentration. In this sixth article, Mark Mayer and Richard Miller detail the mechan$ms and consequences of this activity. fonofropic excifafoy amino acid receptors, most notably those a~tivafed by NMDA, alloy Ca2+ infiux as a result of passive diffusion down ifs conc~izfration gradient. ~etabo~opic receptors trigger an increase in poiyphosphoinositide metabolism, and release of Caa+ from intracellular stores. The increase in ICa’+]i mediated by excitatory amino acids underlies a complex cellular physiology, including the activation of other second messenger systems, and contributes to fhe initiation of long-term potentiation. The id~tification of multiple receptors for excitatory amino acids is now well established. Several potent pharmacological tools have been developed which have allowed the differentiation of N-methyl-D-aspartate (N~A), kainate and AMPA receptors (see Watkins et al. January Tips). Activation of these receptors leads directly to the opening of a group of ion channels which are typified by their different permeabilities to Na+, KC and Caz+ ions (see A:. L. Mayer is Head of the &lit of Neurophysiology and Biophysics, Bldg 36, Room 2.421, NH Bethesda, MD 20892, USA.and R. J. Miller is Professor at the Depnrtmenf of Pharmacological and Physiological Sciences, Universily of Chicago, 947 East 58th St, Ckicago, il. 60637, USA. 0 1990. Elsevier Science I’ubIishers Ltd. (UK)
MacDonald and Nowak, April TiPS). Stimulation of these ‘ionotropic’ receptors underlies rapid excitatory glutamate-mediated synaptic transmission in the CNS {Fig. 1). In addition, the high permeability of the activated NMDA receptor-gated ion channe! to Ca2+ ions results in a large increase in [Ca*+]i (Fig, 2) which may regulate neuronal excitability and also produce certain longer term changes in neuronal behaviour’. Several laboratories have now demonstrated that, rather than gating ion channels, one type of excitatory amino acid receptor activates phospholipase C (and conceivably other molecules) in a G-protein-mediated fashion2s3.
0165 - 6147/9O/!SO2.00
Pierre J. Magistretti V~P-~onfai~~ugcelfs in fke ~eocorfe~ are ~nfrins~cneurons of the bipolar type, wkick release VlP f~zrorfg~r ~nec~lunismsfkaf involve CaZ+ and lipoxyge~use mefabolifes. VlP receptors are coupled to CAMP-generatingsystems that are n~lp~~~edby various ~eurotra~smi~ferssuck us noradre~a~~~e,kista~ine and GABA. Pierre Magistretti reviews the evidence fkaf VIP neurons play an important role in the local regulation of metabolism in the cerebral cortex by stimulafing glycogenolysis and alfering cortical blood flow, Vasoactive intestinal peptide (VIP) is a basic peptide of 28 amino acid residues, amidated at the carboxyl terminus (Fig. I), which was originally identified in the gastrointestinal tract by Said and Mu&. The gene encoding the precursor of human VIP consists of seven exons spanning approximately 9 kb (Ref. 2). Exon four encodes VIP while peptide histidinemethionine (PHM), a peptide sharing sequence homolo~es and activities with VIP, is encoded by exon 5 (Ref. 2). Like various other peptides of gas~intestin~ or endocrine origin, VIP is also present in the nervous system. This article focuses on the properties of VIP as a neurotransmitter of the cerebral cortex and their pharmacological relevance (see Ref. 3 for a more general review). Localization and co-localization In rodent brain, the highest concentrations of VIP are found in certain h~o~al~ic nuclei and in the cerebral cortex (see Ref. 4). in the cortex VIP is contained in a homogeneous population of radially oriented, bipolar interneunms. Because their dendritic arborization diverges only slightly from the main axis of the celle, these intracortical neurons exert very Iocalized input-output functions within radial :ortical ‘columns‘ (Fig. 2). The majority of VIP cortiCal neurons form symmetric synapse@ - a feature generally taken to indicate an inhibitory nature. Such VIP-immunoreactive synapses generally occur on dendritic shafts. In cortical bipolar
neurons, VIP is co-localized with GAPA (3 30% co-localization) and with acetylcholine (> 80% CO1ocalization)s. Thus, physiological and pharmacological interactions between these three neurotransmitters are likely to exist at the pre- and postsynaptic levels. Release Depolarizing stimuli release VIP from neocortical slices in a Ca2+-dependent manner. K+evoked release of VIP is insensitive to Ca2+ channel blockers such as dihydrop~dines, ctlconotoxin and Cd2+, but is inhibited by Nia+, ruling out the involvement of the voltage-sensitive L- and N-type Caa* channel@. By contrast, CNS amine release appears to involve the opening of Ntype channels. Wheth~ this reflects a general difference between amine and peptide release from CNS neurons, or is a peculiarity of the UP-containing intracortical system remains to be determined. Releaseof VIP can also be evoked by 4-~inopy~dine~ a K+ channel blocker. Such release is transsynaptic in nature, since it is largely tetrodotoxin-sensitive; furthermore it involves the formation cf arachidonic acid metabelites of the lipoxygenase pathway since it is decreased by the lipoxygenase inhibitors nordihydroguaiaretic acid, caffeic acid and 5,8,11.,14-eicosatetraynoicacid7. This observation suggests that Caminopyridine evokes the release of one or more cortical neurotransmitters which in turn modulate(s) VIP release via the arachidonic acid cascade. Such modulations of neurotransmitter release by arachidonic acid metabolites of the lipoxygenase pathway have been demonstrated in elegant exper-
iments on identified Aplysia neuron@. In viva studies in cat neocortex indicate that in fact VIP release is under the control of various neurotransmitter systems. Thus GABA, opioids (via y-opioid receptors) and noradrenaline (via fw2-adrenoceptors) inhibit, while cholinoceptor agonists and glutamate stimulate the release of VIP (Ref. 9). Receptors and second messengers Saturable and specific binding of m%IabeIled VIP to cerebral cortical membranes has been demonstrated in several rodent species {see Ref. IO). In the rat neocortex, the highest density of VIP binding sites occurs in layers I, II, IV and VI, as revealed by autoradiographyll; other CNS areas rich in VIP recognition sites are the olfactory bulb, dentate gyrus, subiculum, various thalamic and h~oth~~ic nuclei, locus coeruleus and the pineal gland”. The subependymal layer at the level of all ventricles, the area postrema, subfornical and subcommissural organs are also very rich in binding sites, indicating a possible role for VIP in cerebrospinal fluid homeostasis and blood-brain barrier permeability. The main second messenger pathway activated by VIP receptor occupation is the G protein-adenylyf. ~clase-me~ated increase in CAMP (see Ref. 12). VIP-stimulated CAMP formation has been shown in various species and appears to be subject to modulation by several other cortical neurotransmitters (see below). Studies in purified preparations have revealed that astroeytes and intraparenchymal cerebral cortical microvessels may be the target cells in which CAMP increases are elicited by VIP released from the iutracortical VIP neuronal system (see Ref. 4). The presence of VIPpositive synapses, which are all of the symmetric (i.e. inhibitory) type and which are mainly on dendritic shaft@, demonstrates that neurons and in particular pyramidal cells are also the targets of UP-containing bipolar neurons (Fig. 3). Role in cortical energy me~balism One of the first cellular actions of VIP to be detected was the
TiPS - @2e 1990 fVol. 221
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of CAMP formationI*. While this is an important step in the identification of functional receptors and a useful index for the analysis of potential neurotransmitter (see interactions below), information as to the physiological role(s) of VIP neurons in cerebral cortical circuitry requires (as for any neurotransmitter) the demonstration of cellular actions downstream of second messenger formation. In this context it was instructive to demonstrate that VIP stimulates glycogenolysis in mouse cerebral cortical slices13. Increases in CAMP, by releasing the catalytic subunit of CAMP-dependent protein kinase, trigger various phosphorylation cascades, one of which leads to the conversion of phospho~~ase b to phospho~lase II, a form of the enzyme that is very active in the release of glucose l-phosphate from glycogen (see Box). VIP stimulates cortical glycogenolysis with an ECso of 25 nM; only peptides that share significant sequence homologies with VIP such as peptide histidin&soleucine (PHI) and secretin (13 and nine identical amino acids residues, respectively) exert a similar effect, albeit with lower potencies (EC&s 300 nM and 500 nM, respectively). Human growth hormone-releasing factor (GRF) which, like secretin, shares nine amino acid residues with VIP is inactive; however, only four of these residues are common to the GRF and secretin sequences. This points to a possible role in the activity for the five amino acid positions that are identical in secretin and VIP but not in GRF (Fig. 1). In this context, it will be interesting to examine the effect on cortical glycogen metabolism of helodermin - a peptide with a
29
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high degree of homology with VIP (Fig. I), isolated from the venom of the lizard Gila monste+ The peptide fragments iIP6zs, VIl’1&2s and VIP21-2s do not promote glycogenolysis; nor do other neurotransmitters present in the cerebral cortex, such as GABA,
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glutamate, acetylcholine, somatostatin, cholecystokinin, substance I’, CRF, [Metlenkephalin and [teu]enkephalin*3. The lack of effect of neurotransmitters such as GABA and glutamate is of particular relevance; in contrast to VIP, these neurotransmitters affect
\
’
fig. 2. C~umnar o@~iza~on of VIP-~ntaini~ neurons, and the anafomicaf ~bstrafe for the synergistic effecf of ~mu~n~us acti~~on of noradrene~ic cortical afferents and a group of VIP-containing neurons. Such en arrangement would a/tow for the esfablishment of femporary columnar ‘hot spots’ (white cylinder). VIP, VIP-cxx’ttaining bipolar cell; NA, noradrenergic afferent; Pyr. pyramidal cell furnishing major efferent WM. projections; SA, specific afferent (from the thalamus or from otk corticalregions); subcotiicaf white matter. Cortical layers denoted by reman numerals. (Taken, with permission, from Ref. 4.)
TiPS -June 1990 {Vol. 221 1
tfdamo-cortical fibre
F& 3. Anatomtcatorganization and putative targets of the noradrenatifle- and VIPcontainingneumnst circuits in rat cerebral cottex. Left: noradmnergicfibres originatein locus cue~h?us and pqkct to cerebral cortex where they adopt horizontal trajectory parallel m piat surface. Right:VIP neurons are intrinsic to the cerebral cortex and are orientatedvsrticafiy~~~i~ to pial surface. Astrocytes {A&}, tntr~re~~ai b&cd vessels and neurons such as certain pyr~~at ceit.5 (Pyr) are potenttat target c&/e for VIP neumns. Roman numerals indicate cvrtical layers. VIP neumns can be act&ted by specific afferents (e.g. thalanmcoriical fibres). WM. white matter; St, primary somatosensory cortex. (Taken, with permission, from Ref. 4.)
neuronal excitability profoundly. rapidly and in a rapidly reversible manner by altering selective ion conductances13. Thus VIP-stimulated glycogenolysis is a primary event and is not secondary to energy-demanding changes in neuronal firing rate. Their morphological characteristics (Figs 2 and 3) mean that VIP-containing neurons in the neocortex are ideally positioned to regulate the availabili~ of energy substrates released from glycogen locally, within cortical columns (Fig. 2). More than 90% of VIP-positive cells in the neocortex are bipolar neurons - a cell type ideally suited, because their dendrites span sever21 laminae, to receive specific inputs carried by corticocortical or subcortical afferents; this implies that VIP neurons can translate inputs to a given cortical domain into a local metabolic message, thus contibuting to the metabolic homeostasis of activated cortical areas (see Box and Figs 2 and 3). Noradrenaline, 5-HT and histamine also exert a glycogenolytic action in cerebral cortical slices (see Ref. 15). The morphology of the neuronal circuits that contain these monoamines is strikingly
different from that of VIP intracortical neurons: the axons containing monoamines diffusely innervate the neocortex from subcortically localized perikaryaib. For axons example, noradrenergic originate in the locus coeruleus in the brainstem and enter the neocortex rostrally, adopting a tangential trajectory that spans the entire cortical mantle (Fig. 3). These characteristics allow the noradrenergic system to modulate the availability of energy substrates globally and simultaneously across functionally distinct cortical area@ (Figs 2 and 3). Indeed, it is known that unexpected, nonnoxious sensory stimuli activate the locus coeruleus, increasing the ‘noradrenergic tone’ of the neocortexr6; under these conditions, noradrenaline-induced glysogenolysis would become operative. At the cellular level, VIP- and noradren~ine-induced glycogenolysis has been demonstrated in primary cultures of astrocytes*7, the cell type in which glycogen is predominantly stored in the brain (see Box). Interestingly, the ECso for the effect of noradrenaline, which is mediated by B-adrenoceptors, is 100 times lower in
astrocyte cuhures than in cortical slices {S no vs 500 n&x), while that of VIP is of the same order in the two preparations (5 nM in astrocytes and 25 IIM in slices). The lower ECss for noradrenaline in nrltures is probably due to the absence of significant reuptake, and may reflect its actual potency more accurately. The demonstration of neurotransmitter-mediated ~y~ogenolysis in astrocytes in vitro, if representative of interactions occurring in vim, further supports the notion that neurons and glial cells interact in a functionally coordinated manner, in this case to maintain energy metabolism homeostasis. A role of VIP neurons in cortical energy metabolism is further stressed by the presence of VIPstimulated adenylyl cyclase in microvessel intraparenchymal preparations*8 and by the demonstration of functional VIP receptors on pial vessels that mediate an indometacin-sensitive vasodilationlg. It is, however, likely that these receptors are activated by VIP released from fibres in the walls of pial vessels rather than from the intracortical neurons. Thr functional consequences of the increases in CAMP elicited by VIP in ~~p~n~h~~ cortical microvessels remain to be determined; however, activation of the noradrenergic coeruleo-cortical projection produces changes in blood flow and vascular perand it is possible that meability VIP has similar effects. In this context, the demonstration of an increase in Zdeoxyglucose uptake evoked by VIP application to rat anterior cingulate cortex is of great interest*l. Interactions with other cortical neurotransmitters VIP and noradrenaline have synergistic effects on CAMP production in mouse cerebral cortical slicesz2: in addition to increasing CAMP levels through j3-adrenoceptors, noradrenaline acting at ryl-adrenoceptors markedly potentiates the increases in cAMP elicited by VIP (Ref. 22). This potentiation is inhibited by indometacin and mimicked by PCFacu, strongly suggesting the involvement of prostaglandin formation as a result of r+adrenoceptor activationzs. In functional terms these results indicate that the simul-
TiPS - june 1990 [Vol. 111 taneous release of VIP and noradrenaline within a discrete cortical domain, defined by the intersection of the tangential noradrenergic projection and a group of VIPcontaining intracortical neurons activated by specific afferents, may generate a ‘cortical hot spot’ where drastic increases in CAMP levels would occur (Fig. 2). A correlate to these biochemical observations is the demonstration by Siggins and colleagues that VIP and noradrenaline interact synergistically to depress the spontaneous firing rate of cortical neurons; some of these neurons can be identified as pyramidal cells by antidromic stimulation of the pyramidal tractz4 (Figs 2 and 3). Of the other amines contained in extrathalamic cortical afferent36, histamine, but neither 5-I-IT nor acetylcholine, potentiates the increases in CAMP elicited by VIP through an indometacin-sensitive mechanism25. Activation of GABAB receptors by baclofen also
253 potentiates the effects of VIP on CAMP levels via a Cl--sensitive and indometacin-resistant mechanism*s. Since approximately 30% of VIP-positive neurons also contain GABA (Ref. 5), this observation provides a new example of interactions between co-localized neurotransmitters. The production of CAMP elicited by VIP is modulated by steroid hormones in various areas of the rat brain. Adrenalectomy enhances in a dexamethasonereversible manner VIP-stimulated CAMP formation in the amygdala, septum and hippocampusz6. Furthermore, the potentiation exerted by GABAB receptor agonists on the increases in CAMP elicited by VIP in the neocortex is inhibited by chronic corticosterone treatment27. This effect may be mediated by increased synthesis of lipocortin - a negative modulator of phospholipase AZ. While no modulation by acetylcholine on VIP function has yet been demonstrated in the cortex, choline
Glycogen metabolism, VIP neurons and activation-induced glycolysis Glycogen is the single largest energy reserve of the brain. It is predominantly localized in astrocytes, but has also been identified in choroid plexus and ependymal epithelia, in pericytes and in certain large neurons. At the ultrastructural level, glycogen appears as electron-dense isodiametic (10-30 nm) cytoplasmic j3-particles. Glycogen turnover in nervous tissue is very rapid and the enzymes for synthesis and degradation, i.e. phosphorylase and synthase, have been extensively characterized. The activity of these enzymes is regulated by phosphorylation cascades under the control of intracellular second messengers such as CAMP and Ca2+ (for review see Ref. 1). Evidence has accumulated in recent years that challenges the accepted view of the direct coupling between oxidative phosphorylation and increased neuronal activity. Experiments in humans using positron emission tomography indicate that during sensory stimulation the local increase in cerebral blood flow and in glucose uptake is not matched by increased oxygen consumption 2.3.This implies that the increased metabolic needs that occur in an activated cortical region are met by glycolysis, i.e. by the conversion of glucose into lactate, rather than by oxidative glucose metabolism, despite the fact that the latter pathway produces approximately fifteen times more ATP per glucose molecule. Studies in rats indicate that in fact lactate production increases in the somatosensory cortex following forepaw stimulationa. These observations shed some light on the possible role -of glycogen in cortical energy metabolism: glycogen, mobilized locallv bv VIP released from bipolar cells activated by incoming activity may pro6de an immediate sdurce of glucose for -glycolysi< Glycogen stores would in turn be replenished during the increase in both glucose uptake and cerebral blood flow that accompanies the activation of a functionally defined cortical region. References 1 2 3 4
Magistretti, P. J. (1988) DiubeteMetab. 14,237-246 Fox, P. and Raichle, M. (1986) Proc. Nat!Acad. S:i. USA 83, 1140-1144 Fox, P., Raichle, M., Mintum, M. and Dence, C. (1988) Science 241,462-464 Hossmann, K-A. and Linn, F. (1987) J, Cereb. Blood Flow Metnb. 7, S297
acetyltransferase activity and acetylcholine synthesis are increased by VIP in rat hippocampus2s. In spinal cord cultures containing neurons and glial cells, VIP at subnanomolar concentrations prevents the neurr nal loss that occurs when spontaneous electrical activity has been blocked by tetrodotoxinzg. This effect is mediated through an interaction of VIP with non-neuronal cells, most likely astroglia, since it could be observed in mixed cultures (containing both neuronal and non-neuronal cells) and was absent in purely neuronal cultures2g. Such neurotrophic action of VIP may have pharmacological implications. VIP and sleep mechanisms The intraventricular injection of VIP produces a marked increase in rapid eye movement (REM) sleep and a decrease in the waking time in rats30. Furthermore in rats in which sleep duration is considerably decreased as a result of ptreatment, chlorophenylalanine VIP restores both slow-wave sleep and REM sleep to almost normal levels30. A similar hypnogenic effect of the peptide has been observed in cats, a species in which the capacity of VIP to restore REM sleep is blocked by the a*-adrenoceptor agonist clonidine and augmented by the cholinoceptor antagonist atropineal. Whether such effects relate to the physiological function of the VIP intracortical system remains to be determined; however, the presence of VIP receptors has been demonstrated in various regions of the CNS involved in sleep modulation, such as the locus coeruleusl’. q
cl
q
The morphological characteristics of the VIP-containing intracortical system imply that the cellular actions of VIP are exerted with high spatial resolution. These actions appear to converge into a metabolic function, as is indicated by the effects of VIP on energy metabolism and blood flow. cAMI’ and prostanoids are two effector pathways that translate (and amplify in the case of prostanoids) VIP receptor occupation into a cellular effect. Arachidonic acid
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metabolites in particular may play a crucial role in modulating VIP circuits, since prostaglandins enhance a post-synaptic effect of VIP, i.e. cAMP formation, and lipoxygenase metabolites are involved in VIP release from presynaptic sites. The development of potent antagonists and nonpeptide analogues of VIP that can cross the blood-brain barrier will make an important con~bution to understanding of the physiology of the VIP intracortical neuronal system, and of the potential for pharmacoIogica1 intervention in cortical energy metabolism under conditions such as ischaernia or aging. Acknowledgements Research in P@l’s laboratory is supported by the Swiss National Science Foundation (Grant No. 31-26427.89). The author is gratefuI to MS M. Emch for expert secretarial help.
1 Said. S. I. and Mutt, V. (1970) Sciexe 169.1217-1218 2 Linder, S. et at. (1987) Proc. Nafi Acad. Sci. USA 84,6OS-609 3 Said, S. I. and Mutt, V., eds (1988) Ann. NY Acad. Sci. 527,1-691 4 Magistretti, P. J. and Morrison, J. H. (1988) Neuroscience 24.367-378 5 Peters, A. and Harriman, K. M. (1988) J. Camp. Neural. 267,409-432 6 Martin, J-L. and Magi&ret& P. J. (1989) Neuro5~eace 30,423-X+1 7 Martin, J-L. and Magistretti, P. J. (1989) J. Neurosci. 9, 253&2542 8 PiomeUi, D. et ol. (1987) Nature 328, 38-%3 9 Wang, J. Y., Yaksh, ‘I’. L., Harty, G. J. and Go, V. L. W. (19%) Am. J, Pkysiol. 250, RlOPRlll 10 Staun-Olsen, P. et at. (1982) [, Neuro&em. 39,1242-1251 11 Martin, J-L., Die& M. M., Hof, P. R., Palacias, J. M. and Magistretti, P. J. (1987) Neuroscience 23, 539-565 12 Said, S. I., ed. (1982) Advances in Peptide Hormone Research Series, pp. 1-512, Raven Press 13 Magistretti, P. J., Morrison, J. H., Shoemaker, W. J., Sapin, V. and Bloom, F. E. (1981) Proc. Nat1Acad. Sci. USA 78, 6535-6539 14 Robberecht, P. et al. (1984) FEBS Lett. 166.277-282 15 Magistretti, P. J. (1988) Diabete Metab. 14,237-246 16 Foote, S. L. and Morrison, J. H. (1987) Ann. Rev. hieurosci. l&67-95 17 Magistretti, P. J., Manthorpe, M., Bloom, F. E. and Varon, S. (1983) Regul. Pept. 6, 71-80 18 Huang. M. and Rorstad, 0. P. (1984) J. Neurockcm. 43, 849-856 19 Wei, E. I’., Kontos, H. A. and Said, 5.1. (1980) Am. 1. Pkysiol. 239, H765-H768 20 Raichle, M. E., Nartman, B. K., Eichling,
J. 0. and Sharpe, L. G. (1975)Proc.Nat1 Acad. Sci. USA 72, 3726-3730 21 McCulloch, J. and Kelly, P.A.T. (1983) Nafirre 304,438-440 22 Magistretti, I’. J. and Schorderet, M. (1984) Nature 308,280-282 N., Schorderet, M. and 23 Schaad, Magistretti, P. J. (1987) Nature 328, 637-640 24 Ferron, A., Siggins, G. R. and Bloom, F. E. (1985)Proc.Nafl Acad. Sci. USA82, 8810-8812 25 Schaad, N. C., Schorderet, M, and Magis~tti, P. J. f1989) f. ~ei~roc~zesr. 53, 1941-1951 26 Harrelson, A. L., Rostene, W. and
27
28 29
30 31
McEwen, 8. S. (1987) J. Nerrrockem. 48, 1648-1655 Duman, R. S., Karbon, E. W., Harrington, C. and Enna, S. J. (1986) 1. Netirocke~. 47,800-810 Lapchak, P. A. and Collier, 3. (1988) f. Neurockem. 50,58-64 Brenneman, D. E., N&e, E. A., Foster, G. A., d’Autremont, S. W. and Westbrook, G. L. (1987) 1. Cell Biol. 104, 1603-1610 Riou, F., Cespuglio, R. and Jouvet, M. (1982) Nearo~e~f~~es2, 26%277 Jimenez-Anguiano, A., Prosp&oGarcia, 0. and Trucker-Colin, R. (1989) Sot. Neurosci. Abstr. 15, 242
xcitat~~ a ino acid receptors, second messengers and iegulation of intra~eii~lar a*+ in mammalianW Mark L. Mayer and Richard J. Miller As we have learnt from earZier arficles in our series on the pharmacology of excitatory amino acids, neurons andglia express several subtypes of excitatory amino acid receptor, the activation of which increases intracellular free calcium ion concentration. In this sixth article, Mark Mayer and Richard Miller detail the mechan$ms and consequences of this activity. fonofropic excifafoy amino acid receptors, most notably those a~tivafed by NMDA, alloy Ca2+ infiux as a result of passive diffusion down ifs conc~izfration gradient. ~etabo~opic receptors trigger an increase in poiyphosphoinositide metabolism, and release of Caa+ from intracellular stores. The increase in ICa’+]i mediated by excitatory amino acids underlies a complex cellular physiology, including the activation of other second messenger systems, and contributes to fhe initiation of long-term potentiation. The id~tification of multiple receptors for excitatory amino acids is now well established. Several potent pharmacological tools have been developed which have allowed the differentiation of N-methyl-D-aspartate (N~A), kainate and AMPA receptors (see Watkins et al. January Tips). Activation of these receptors leads directly to the opening of a group of ion channels which are typified by their different permeabilities to Na+, KC and Caz+ ions (see A:. L. Mayer is Head of the &lit of Neurophysiology and Biophysics, Bldg 36, Room 2.421, NH Bethesda, MD 20892, USA.and R. J. Miller is Professor at the Depnrtmenf of Pharmacological and Physiological Sciences, Universily of Chicago, 947 East 58th St, Ckicago, il. 60637, USA. 0 1990. Elsevier Science I’ubIishers Ltd. (UK)
MacDonald and Nowak, April TiPS). Stimulation of these ‘ionotropic’ receptors underlies rapid excitatory glutamate-mediated synaptic transmission in the CNS {Fig. 1). In addition, the high permeability of the activated NMDA receptor-gated ion channe! to Ca2+ ions results in a large increase in [Ca*+]i (Fig, 2) which may regulate neuronal excitability and also produce certain longer term changes in neuronal behaviour’. Several laboratories have now demonstrated that, rather than gating ion channels, one type of excitatory amino acid receptor activates phospholipase C (and conceivably other molecules) in a G-protein-mediated fashion2s3.
0165 - 6147/9O/!SO2.00