title: Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.
abstract: BACKGROUND
  Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5).
  
  
  RESULTS
  To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2). Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/-) and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.
  
  
  CONCLUSIONS
  This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Padmesh S
authors.initials: PS
authors.lastname: Rajput
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Kharmate
authors.forename: Michael
authors.initials: M
authors.lastname: Norman
authors.forename: Shi-He
authors.initials: SH
authors.lastname: Liu
authors.forename: Bhagavatula R
authors.initials: BR
authors.lastname: Sastry
authors.forename: Charles F
authors.initials: CF
authors.lastname: Brunicardi
authors.forename: Ujendra
authors.initials: U
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D064026:Calbindins; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000172:deficiency* / Q000235:genetics*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D064026:Calbindins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D016194:Receptors, N-Methyl-D-Aspartate; D017481:Receptors, Somatostatin; D064030:S100 Calcium Binding Protein G; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse