Out of Africa: First International Meeting

meeting report ot many international neuroscientific meetings can boast Out of Africa: First InternationaIMeeting N of incorporating the following subjects in their programme: the neurochemical aspects of the brain of chameleon (Chamaeleo jacksoni); the carotid sinus and cerebral vessels of the Maasai giraffe (Giraffa camelopardalis); and the control of scent-behavior in the sub-saharan rodent, Meriones shawl However, the first formal meeting of the Society of Neuroscientists of Africa (SONA)* brought together expertise on the above with that of an international blend of scientists. The science also included current developments in understanding common neurodegenerative diseases, mechanisms in brain blood-flow, epilepsy and attention-deficit disorders and their impact in Africa. At the opening address, R. Leakey (now director of the Kenya Wildlife Services, Kenya) discussed how Africa has made a profound contribution to cognitive and behavioural neuroscience. Was the brain of primitive man as advanced as that of modern man? In his characteristic style, Leakey related the fascinating story of the Turkana boy 1, noting that impressions from the skull of the fossil boy indicated the existence of a full-size brain with appropriate development and formation of the cranial and presumably the cerebral arteries. The scientific sessions were begun by M. Zigmond (University of Pittsburgh, Pittsburgh, PA, USA), who emphasized the vital link between the laboratory and clinic, as well as between developing and developed nations. In recounting the medical history of parkinsonism he reminded the audience how the discovery of reserpine in a developing country (India) led ultimately to investigations on postmortem brain tissue performed in a developed country (Austria). Zigmond also presented recent evidence suggesting increased turnover of dopamine in surviving nigral neurons of the parkinsonian brains, and that under certain conditions the transmitter itself is neurotoxic. The presen*The SONA meeting was held March 8-11, 1993 in Nairobi, Kenya.

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tation sparked an interesting dis- of Alzheimer's disease (AD) and R. IV. Kalaria cussion on the etiology and preval- suggested that cerebral amyl- Deptsof Neurolo~ ence of parkinsonism in Africa. oidosis is central to the patho- and Neurosciences, W. Matuja (University of Dar-es- genesis of AD. In distinguishing CaseWestern Saalam, Tanzania) suggested that AD from normal aging, R. Kalaria ReserveUniversity, Cleveland,OH most cases of parkinsonism seen in (Case Western Reserve Univer- 44106, USA. the Tanzanian clinics were of sity, Cleveland, OH, USA) conM. J. Zigmond younger patients and were post- sidered evidence that cerebral Oeptof encephalitic in nature. However, it amyloid angiopathy is a different Neuroscience, is probable that idiopathic Parkin- process from amyloid deposition in Universityof son's disease exists in the indigen- the neuropil. He also considered Pittsburgh, ous population 2, but has not yet whether AD exists in Africa among Pittsburgh, PA 15260, been widely described. the indigenous population. Cur- USA. It was further suggested that rently, there is only a single study J. K. Kimani some cases of parkinsonian-like that has addressed this question. Secretary-General, syndromes result from neuro- Osuntokun et al. (Ref. 4) recently Societyof toxicity by ingestion of certain local reported that dementia of the AD Neuroscientistsof plants ~. B. Meldrum (Institute of type was absent or had a very Africa (SONA),Dept of HumanAnatomy, Psychiatry, London, U K ) d r e w low incidence among Nigerians, Universityof Nairobi, attention to the existence of a a finding that warrants further PO Box30197, variety of exogenous excitotoxins investigation. L. Houenou (Bowman Nairobi, Kenya. such as domoic acid, which might Grey University, Winston-Salem, act through similar mechanisms NC, USA) reported on the role of but be responsible for a number of growth factors in early motoneuron disorders. This theme was further cell death and discussed the work expanded on by other members of done in collaboration with R. this international team of neuro- Oppenheim on the newly disscientists (F. Javoy-Agid, M. covered profound effects of brainYoudim, R. Schwarcz), who derived growth factor (BDNF) on discussed free radicals and the development of motoneurons excitotoxicity in the etiology and of the spinal cord. Participants from the African treatment of neurodegenerative diseases. For example, Youdim nations clearly demonstrated that, (Technicon University, Haifa, despite limited funding and meager Israel) described how iron was resources for their research, solid vital to brain metabolism and neuroscience prevails in Africa. It implicated its deficiency or mis- was also readily evident that all metabolism in chronic neuro- facets of neuroscience, from moldegenerative disease and nu- ecular studies to systems neurotritional disorders. However, he science, are operative, albeit on a also documented the redistribution small scale. Among the morphoof stored iron from the cortical logical studies presented, J. mantles to subcortical areas during Bhattacharjee (Egerton Univerbrain development, suggesting an sity, Njoro, Kenya) gave an interimportant role for this process in esting account of the appearance the selective vulnerability of the of acetylcholinesterase (AChE)stained varicosities associated with • nigral dopamine neurons. Key issues involved in the cur- amacrine cells in developing chick rent understanding of brain aging retina. He suggested that amacrine and other neurodegenerative dis- cells, which release excitatory orders were also discussed. P. amino acids, play a prominent role Brown's (NINDS, Bethesda, MD, in the synaptic stratification of the USA) offerings on human spongi- inner plexiform layer and that form encephalopathy reviewed the AChE is intimately involved in the evidence for the hypothesis, that synaptogenic process. With an mutations in the prion protein emphasis on neurochemistry, B. contribute significantly to the Davidson (Wits Medical School, pathology. K. Kosik (Harvard, Parktown, RSA) described the role Boston, MA, USA) provided an of long-chain polyenoic fatty acids account of the current under- (PFAs), precursors of the eicostanding of the neuronal pathology sanoids, in striatal dopaminergic © 1993, ElsevierSciencePublishersLtd, (UK)

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neurotransmission. Unlike other mammals, domestic cats (and possibly the wild ones of the African plains!), which lack the first enzyme in the synthetic pathway of PFAs, linoleoyl-CoA desaturase (A6-desaturase), are dependent on a dietary source of PFAs. Longterm dietary deprivation of PFAs in domestic cats induces motor deficits and a 'catatonia' that may correlate with changes in striatal dopamine release and structure and could have implications in diseases such as Parkinson's disease. In this nutritional context, W. Benegelloun (Mohammed V University, Rabat, Morocco) presented convincing evidence that long-term protein malnutrition in young, weaned rats resulted in behavioral deficits that persisted even after rehabilitation to a normal diet. A series of behavioral tests showed that the learning capacities of previously proteinmalnourished rats were affected, particularly in complex tasks, with a more profound effect in females than males. While the current interest in nitric oxide is raging high, how does its nearest neighbor, nitrous oxide, work? M. Gilman and F. Lichtigfeld (South African Brain Research Institute, Johannesburg, RSA) chaired a refreshing symposium on the therapeutic uses and abuses of nitrous oxide but more interestingly presented evidence that nitrous oxide might act directly on opiate receptors in the brain. R. Butterworth (University of Montr6al, Montr6al, Canada) reviewed the current understanding of hepatic encephalopathy in chronic liver disease that may result from viral infections, schistosomiasis or alcoholism. This Acknowledgements was a subject appropriate to the SONA wishesto African setting since, as is the case thank UNESCO, 18RO, the in some developed nations, one International Society of the problems in developing for Neurochemistry, countries is alcohol abuse accomthe Society for panied by malnutrition. As in other Neuroscience, the countries of Africa, the use of European highly toxic illegal brews such as Neuroscience changaa (potato liquor) and mnazi Associabon, the (palm wine) is widespread in some Association of East African communities. PreNeurosc~ence Departments (US), vailing evidence suggests that Case Western hepatic encephalopathy results ReserveUniversity from high concentrations of and the University of ammonia that disrupt both exNairobi for generous citatory and inhibitory neurosupport. transmission. The treatment and 298

management of the encephalopathy in chronic liver disease rely on the reduction of blood ammonia through diet and use of lactulose or neomycin. The programme very fittingly included a symposium on the neurobiology of acquired immune deficiency syndrome (AIDS), or more apropos the neuroscience of human immunodeficiency virus (HIV) infection, co-chaired by P. Kennedy (University of Glasgow, Glasgow, UK) and P. Luthert (Institute of Psychiatry, London, UK). Recent estimates by the World Health Organization (WHO) indicate that more than 80% of people infected with HIV live in developing countries. The opening talk of the symposium by A. Ndinya-Achola (Kenyatta Hospital, Nairobi, Kenya) provided an informative epidemiological view of HIV seropositivity in East Africa and revealed that heterosexual transmission (largely through prostitutes) was the main mode of HIV infection. D. Ndetei's (University of Nairobi, Nairobi, Kenya) studies supported by WHO suggested that there was a high prevalence of neuropsychiatric disturbances with major depression as the predominant finding in symptomatic HIVseropositive patients. Luthert described neuronal loss in simian immunodeficiency virus (SIV)infected nonhuman primates and related it to the profound loss of pyramidal cells in some cortical layers in frontal lobes of patients with AIDS dementia complex. While the virus does not directly infect neurons it is thought that the neuronal loss evident in HIV infection of the CNS results from the production of endogenous excitotoxins, such as quinolinic acid, by glia (R. Schwarcz, NIDA, Baltimore, MD, USA). Although the incidence of subacute demyelinating polyradiculopathy in the Kenyan HIV-positive patients is also high (A. M. Adam, University of Nairobi, Nairobi, Kenya), what was surprising was the previously unknown association of mammillary body pathology, similar to that in Wernicke's encephalopathy, in a large proportion of HIV patients. That Africa can offer such absorbing problems to study was illustrated in a remarkable twolecture session by K. Kristensson (Karolinska Institute, Huddinge, Sweden) and M. Bentivoglio

(University of Verona, Verona, Italy). They presented their elegant studies on the effects on the CNS of the hemoflagellate

Trypanosoma brucei brucei (Tbb) involved in the cause of trypanosomiasis or African sleeping sickness. Kristensson reported that Tbb produces a factor that induces expression of the class I major histocompatibility iMHC) antigen that can stimulate dorsal root ganglion cells in culture to produce a y-interferon-like molecule. This in turn then stimulates proliferation and growth of the parasite. Working with an experimental model of trypanosomiasis, Bentivoglio described results indicating impaired c-los gene expression in the suprachiasmatic nucleus of the hypothalamus. She also noted increased expression of class I MHC antigen in the paraventricular nucleus of the hypothalamus. These observations lend support to the hypothesis that changes in hypothalamic nuclei are responsible for alterations in the circadian rhythm that results in the sleep sickness. The last symposium of the week on growth factors and their mechanisms of action through ras proteins (G. Landreth, Case Western Reserve University, Cleveland, OH, USA) and trk receptors (S. Feinstein, University of California, Santa Barbara, CA, USA) also demonstrated how materials from Africa could be useful in neuroscience research elsewhere. J. Fallon (University of California, Davis, CA, USA) recounted the anatomical distribution of growth factors in brains of nonhuman primates such as the vervet monkey (Cercopithecus aethiops). This work was done in collaboration with James Kimani and colleagues at the University of Nairobi. In an effort to promote such collaborations, discussions were also held during the meeting with a group of local students interested in pursuing doctoral studies in neuroscience. To facilitate this, a programme is being developed through the Association of Neuroscience Departments in North America. As aptly reflected by K. Thiaru (Medical Advisor, Commonwealth Secretariat, UK and Kenya) in his closing remarks, the delegates left the meeting with confidence and joy: that a child was born, and in TINS, Vol. 16, No. 8, 1993

order for it to thrive, it should be nurtured. In this 'Decade of the Brain' neuroscience in Africa should be pursued with greater force. Just as there is always room for (one) more when one rides the matatu to town or the airport,

there is room for neuroscientists to join this cause.

Selected references 1 Leakey, R. (1992) Origins Recon-

sidered: in search of what makes us Human, Doubleday 20suntokun, B. O. et aL (1987)Acta

Neurol. Scand. 75, 13-21 3 Kokwarou, J. O. (1976) Medicinal Plants of East Africa, East African LiteratureBureau 40suntokun, B. O., Ogunniyi,A. O., Lekwauwa, G. U. and Oyediran, A. B. O. O. (1991) Trop. Geogr. Med. 4, 345-351

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Are neostriataldopaminereceptorsco-localized? D. James Surmeier, Anton Reiner, Michael S. Levine and Marjorie A. Ariano Thepostsynaptic effects of dopaminein the neostriatumaremediated by five G-protein-coupled receptors. The extent to which these receptors are co-localizedin neostriatal neurons has become controversial. This debate has far-reaching implications for treatment strategies in disordersof dopaminergic signaling, such as Parkinson's disease andschizophrenia. This reviewexamines the molecular and cellular evidence for and against co-localization, includingnew information derivedfrom single-cell mRNA amplification andpatchclamping of isolated neurons. It is concludedthat this evidenceis largely consistent with co-localization of functionally significant receptors of the DI and D2 familiesin the majorily of neostriatal efferent neurons. This conclusion has important implications for parallelprocessing modelsof the neostriatum.

Understanding dopaminergic mechanisms in the neostriatum is of broad clinical relevance. Many neurological disorders are thought to reflect disruptions in dopaminergic signaling. Parkinson's disease, schizophrenia, Tourette's syndrome and addictive types of behavior are commonly encountered neurological dysfunctions with dopaminergic involvement. For example, the near total loss of the dopaminergic innervation of the striatum is the cause of Parkinson's disease (PD) - a disease that afflicts roughly one in a thousand adults ~. Although the etiology of affective disorders, such as schizophrenia, and addictive types of behavior are less well understood, both sorts of disorder appear to result from alterations in the mesolimbic dopaminergic pathway innervating ventral striatum and frontal cortex 2,3. The design of rational pharmacological therapies for these syndromes hinges upon knowing the distribution of neostriatal dopamine receptors and the functional consequences of their activation (or blockade). In particular, it is important to determine whether the postsynaptic receptors mediating the actions of dopamine are segregated in different neuronal populations or are co-localized within the same neurons. Although most of the relevant experimental evidence bearing on colocalization comes from work with rodents, there is little reason to believe that primate neurons differ significantly on this issue4.

dopamine is capable of acting through at least five G-protein-coupled receptors, labeled D1-Ds, with the D2 and D3 receptors each exhibiting two splice variants. These receptors can be classified pharmacologically into a Dl-family (D1, D5 or DIA, D18) and a D2-family [D2short (D2s), D21ong (D2L), D3short (D3s!, D3 lone (D3L), D4], based upon their affinities for classical' D1 and D2 ligands. Each of these receptors, in varying levels of abundance, is found in the neostriatum. In principle, there are two ways in which these receptors could modulate the behavior of neostriatal neurons. The first is through presynaptic control of transmitter release. Under normal conditions, the prindpal excitatory inputs to the neostriatum come from the cerebral cortex and thalamus (see Ref. 8 for a review). Fluctuations in these inputs govern the transitions between quiescent and active modes in most neostriatal neurons. Dopamine does not appear to modulate the corticostriatal and thalamostriatal pathways presynapticallyg; however, dopamine is capable of modulating its own release through autoreceptors 10. The second way in which dopamine could modulate cellular behavior is through postsynaptic mechanisms. As discussed below, there is considerable evidence for postsynaptic dopamine receptors. These receptors couple to signaling pathways that are capable of influencing a wide variety of cellular targets, including ion channels and transcription factors. This article focuses on this group of receptors and whether there is evidence that single neostriatal neurons express more than one subtype.

D. JamesSurmeier andAnton Reinerare at the Deptof Anatomyand Neurobiology, Collegeof Medicine, Universityof Tennessee,Memphis, TN38163, USA, Michae/S. Levineisat the Deptof Psychiatry,University of Californiaat Los Angeles,CA90024, USA,andMarjorieA. Arianois at the ChicagoMedical School,Deptof Neuroscience, 3333 GreenBayRd, Chicago,IL 60064, USA.

Studies examining the localization of receptor mRNA and protein The extent to which different dopamine receptors are expressed by the same neostriatal neuron has been controversial. The principal neuron in the neostriatum is the GABAergic medium spiny projection neuron. These neurons send axons to the globus pallidus or the substantia nigra or both. Those neurons with axons terminating in the globus pallidus express the opioid peptide enkephalin, A heterogenous group of dopamine receptors whereas those with axons terminating in the subUntil recently, it was thought that the actions of stantia nigra express the neuropeptides substance P dopamine were mediated by only two receptors, and dynorphin 11. The in situ hybridization studies of referred to as D~ and D2. Molecular cloning studies Gerfen et aL ~2 and Le Moine et aL ~3 suggest that in the past few years have dramatically altered this substance-P-containing neurons express D1 recepviewpoint 5-7. These studies have revealed that tor mRNA, but little or no D2 receptor mRNA, and TINS, VoL 16, No. 8, 1993

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