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Phosphoinositide Second Messenger System Is The Journal of Neuroscience, August 1993, 13(E): 3300-3308 Phosphoinositide Second Messenger System Is Enriched in Striosomes: lmmunohistochemical Demonstration of lnositol 1,4,5=Trisphosphate Receptors and Phospholipase C ,8 and y in Primate Basal Ganglia Majid Fotuhi,’ Ted M. Dawson,1s2 Alan H. Sharp,’ Lee J. Martin,3 Ann M. Graybiel,4 and Solomon H. Snyder’ ‘Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry, *Department of Neurology, and 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and 4Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 The neurochemical organization of the basal ganglia has rons embedded in the medullary layer between the putamen been studied extensively with respect to neurotransmitters, and the globus pallidus. neuropeptides, and their receptors. The chemoarchitecture These observations demonstrate that the phosphoinosi- of the striatum has been found particularly striking, because tide second messenger system is selectively enhanced in it distinguishes many substances by their relative distribu- neuronal subsystems of the basal ganglia, including strio- tions within the striosome and matrix compartments of the somes, and suggest that signaling by phosphoinositide path- striatum. Very little is yet known about the differential dis- ways elicits discrete effects on input-output processing by tribution of second messenger systems in the basal ganglia, the basal ganglia. however, and no information is available about whether the [Key words: phosphoinositide, phospholipase C, striatum, distribution of second messenger systems is related to the striosome, primate] prominent neurochemical compartmentalization of the stria- turn. We have examined the distribution of the phosphoinosi- An important organizational principle of the basal ganglia in- tide second messenger system in the primate basal ganglia volves differentiation of the neostriatum into compartments and substantia nigra, as detected with polyclonal antisera referred to as striosomes and matrix (Graybiel and Ragsdale, against the inositol 1,4,5-trisphosphate receptor (IP,R), and 1978).Neurons in striosomesand matrix differ in their ontogeny monoclonal antisera against phospholipase C @ (PLC@) and as well as in their afferent and efferent connections. Neurons in phospholipase C y (PLOy). striosomes mature earlier than those in the matrix, and the In the striatum, immunostaining for each of the three pro- striosomal system receives denseinputs from prefrontal orbi- teins was present predominantly in medium-sized neuronal toinsular parts of the cortex, whereasthe matrix input predom- perikarya and in the neuropil. Circumscribed zones of en- inantly originates in other regionsincluding sensorimotor cor- hanced IP,R, PLC& and PLCr immunoreactivity appeared in tical areas (Fishell and van der Kooy, 1982; Gerfen, 1984; a background of generally weaker staining, and these zones Ragsdaleand Graybiel, 1988, 1990;Flaherty and Graybiel, 1991). corresponded to striosomes as identified by calbindin D,,, Striosomal neuronsappear to receive their dopamine-contain- and substance P immunostaining in adjacent sections. Thus, ing input mainly from densocellularislands in ventral parts of the richest representation of the phosphoinositide system the substantianigra pars compacta (SNc) and to project mainly in the primate striatum appears to be in striosomes. back to medial nigral regions. Neurons of the striatal matrix, In the substantia nigra pars compacta, neurons and neu- by contrast, receive their dopamine-containing inputs mainly ropil were immunopositive, but in the substantia nigra pars from other neurons of the nigral complex and project mainly reticulata and in each segment of the globus pallidus, im- to the external (GPe) and internal (GPi) segmentsof the globus munostaining was mainly confined to the neuropil. Perikaryal pallidus (GP) and to the substantia nigra pars reticulata (SNr) PCL-r immunoreactivity in the absence of detectable PLC/3 (Graybiel et al., 1979;Gerfen, 1984;Donoghue and Herkenham, or IP,R immunolabeling was found in the magnocellular neu- 1986; Gerfen et al., 1987; Jimtnez-Castellanos and Graybiel, 1987, 1989; GimCnez-Amaya and Graybiel, 1991). Striosomesand matrix differ also in their content of neuro- Received Apr. 21, 1992; revised Nov. 19, 1992; accepted Jan. 12, 1993. transmitters and receptors. For instance, striosomesare selec- This work was supported by USPHS Grant MH-18501, Research Scientist tively enriched in limbic-associatedmembrane protein (LAMP) Award DA-00074 to S.H.S., Javits Award NS-25529 to A.M.G., and a gift from (Chesseletet al., 1991), whereasthe matrix is enriched in cal- Bristol-Myers-Squibb. T.M.D. was supported by a Pfizer postdoctoral fellowship and grants from the Dana Foundation, the French Foundation for Alzheimer’s bindin D,,,, AChE, ChAT, somatostatin, and tyrosine hydrox- Research, and the American Academy of Neurology. M.F. was supported in part ylase(TH). Opiate and dopamine D,-like receptorsare enriched by Fonds pour Formation de Chercheurs et L’Aide rl La Recherche (FCAR) of Quebec, Canada. We thank Dr. Sue Goo Rhee for a generous gift of antisera to in striosomes,whereas dopamine D,-like and some muscarinic phospholipase C @ and y. choline& receptors predominate in the matrix (Pert et al., Correspondence should be addressed to Dr. Snyder, Departments of Neuro- 1976; Herkenham and Pert, 1981; Graybiel et al., 1986; Joyce science, Pharmacology and Molecular Sciences, and Psychiatry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. et al., 1986; Bessonet al., 1988; for a review, see Graybiel, Copyright 0 1993 Society for Neuroscience 0270-6474/93/l 33300-09%05.00/O 1990). There are also regional variations in these striosomel The Journal of Neuroscience, August 1993, 13(E) 3301 matrix distributions for individual transmitter-related markers perature. After three washes of 10 min each in TBS, the blots were (Graybiel and Ragsdale, 1978; Besson et al., 1990; Martin et developed using 4-chloro- 1-naphthol as the substrate. al., 1991) and species differences as well. Immunohistochemistry. All steps were carried out in TBS and im- munostaining for each antiserum was performed under the following This differential distribution of multiple neurotransmitter- conditions. Serial transverse sections were perrneabilized in 0.4% T&on related elements in striosome and matrix compartments sug- X- 100 for 30 min and pretreated for an additional 30 min in 4% normal gests functional specificity, but it is difficult to relate them to goat serum (NGS) or, for sections to be incubated in goat IP,R anti- specific extrapyramidal functions (Albin et al., 1989). Neuro- serum, in normal rabbit serum (NRS) or, for sections to bc incubated in PLC& PLCr, or calbindin D,,,, in normal horse serum (NHS) con- transmitters, however, act through only a few second messenger taining 0.1% Triton X-100. They were then incubated overnight in systems, with the CAMP and phosphoinositide (PI) systems pre- primary antiserum (see above for dilutions) containing 2% NGS (or 2% dominating, so what seems complex at the neurotransmitter NRS for IP,R or 2% NHS for PLCP, PLCr, or calbindin D,,,), 0.1% level may be systematically ordered at the second messenger Triton, and 0.02% sodium azide at 4°C. level. PI markers, such as the inositol 1,4,5-trisphosphate (IP,) After three washes of 10 min each in TBS, sections were incubated with biotinylated secondary anti-goat or anti-rabbit antibodies (1:200) receptor (IP,R) and protein kinase C (PKC), and markers of the (ABC elite kits of Vector Laboratories, Burlingame, CA) in 0.1% Triton CAMP system, such as 3H-forskolin binding, are differentially X-100 at room temperature for 1 hr. Sections were washed 3 x 10 min distributed in the brain with a number of complementary lo- in TBS and incubated in an avidin-biotin-peroxidase complex (1:50) calizations (Worley et al., 1986a,b, 1987, 1989). In the extra- for 45 min. Finally, they were washed (3 x 10 min) and developed in the presence of 0.02% hydrogen peroxide with diaminobenzidine as the pyramidal system, PI markers occur in high densities in the chromogen. Sections were rinsed thoroughly and mounted on subbed corpus striatum and the SNr. The neuroanatomical distributions glass slides, dehydrated, and coverslipped with Permount. Striosomes of phospholipase C (PLC) (Gerfen et al., 1988) PKC (Huang et were identified as zones with few neurons expressing calbindin D,,, or al., 1988; Saito et al., 1988; Yoshihara et al., 1991) and IP,R enkephalin, or by enrichment in substance P-like immunoreactivity. (Nakanishi et al., 1991; Sharp et al., in press) have been de- Controls for immunocytochemical staining for the IP,R antibody were prepared by preadsorbing with excess (loo-fold) IP,R protein. scribed in the rat brain, but these messenger distributions have Control sections for antisera to PLCP, PLCr, calbindin D,,,, TH, sub- not been mapped in primate, in which the striatum and sub- stance P, and met-enkephalin were prepared by incubating sections in stantia nigra are highly differentiated as compared to these regions the appropriate pre-immune serum, respectively. in rat. In particular, the relationship of the PI system to the The density of immunostaining for IP,R, PLC& and PLCy was ar- bitrarily assigned value based on visual inspection of sections from all striosome and matrix
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