title: Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's disease.
abstract: Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.
authors.affiliation: Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS at the European Center for Brain Research, via del Fosso Fiorano 64, 00143 Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.forename: Zena
authors.initials: Z
authors.lastname: DeMarch
authors.forename: Vincenza
authors.initials: V
authors.lastname: D'Angelo
authors.forename: Maria
authors.initials: M
authors.lastname: Morello
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martorana
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sancesario
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
mesh_terms: D000818:Animals; D064032:Calbindin 2; D064026:Calbindins; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009474:Neurons / Q000145:classification / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors
chemical_list: C576511:Calb2 protein, mouse; C576512:Calb2 protein, rat; D064032:Calbindin 2; D064026:Calbindins; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid