Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington’s Disease Transgenic Mice Padmesh S. Rajput1, Geetanjali Kharmate1, Michael Norman2, Shi-He Liu2, Bhagavatula R. Sastry3, Charles F. Brunicardi2, Ujendra Kumar1* 1 Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada, 2 Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America, 3 Neuroscience Research Laboratory, Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada 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). Methods and Findings: 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-a and calcineurin in SSTR1/52/2 and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidy- linositol 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. Citation: Rajput PS, Kharmate G, Norman M, Liu S-H, Sastry BR, et al. (2011) Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington’s Disease Transgenic Mice. PLoS ONE 6(9): e24467. doi:10.1371/journal.pone.0024467 Editor: Joseph Najbauer, City of Hope National Medical Center and Beckman Research Institute, United States of America Received April 27, 2011; Accepted August 10, 2011; Published September 2, 2011 Copyright: 2011 Rajput et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from Canadian Institute for Health Research (MOP-10268 and MOP-74465 to UK) and NIH Grant (RO1-DK46441 to FCB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ujkumar@interchange.ubc.ca Introduction Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by mutation in the huntingtin (Htt) gene and characterized by progressive chorea and impaired cognitive function [1,2]. Genetic abnormality of expanded polyglutamine repeat sequence is confined in the coding region of a gene IT15 located on chromosome 4 encoding the Htt protein [3,4]. The length of CAG repeat is one of the factors that plays an important role in the onset of HD symptoms [5,6]. Pathological characteristics of the disease are the intranuclear inclusion of mutated Htt and neostriatum atrophy and gliosis. In addition to genetic mutation and histopathological hallmarks, the critical determinant of HD is the degeneration of medium size spiny neurons (MSNs) expressing c-aminobutyric acid (c-GABA), N-methyl-D-aspartic acid receptors (NMDARs) and dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32). In contrast, in striatum, a subset of neuronal population consisting of medium sized aspiny interneurons positive to somatostatin (SST), neuropeptide Y (NPY) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)/brain nitric oxide synthase (bNOS) are selectively spared [7,8]. In addition, the expression of calbindin D-28K is increased in HD patients, transgenic mouse models and quinolinic acid (QUIN)-induced excitotoxicity [9,10,11]. Activation of NMDARs in striatum mimics the pathological, neurochemical and behavioral changes of HD [12]. Furthermore, the analysis of HD patient’s postmortem brain reveals the degeneration of NMDAR-positive neurons and association with the pathogenesis in HD [13,14]. NMDARs are composed of two subunits of NR1 and two subunits of NR2A, NR2B or NR2C [15,16]. Previous studies have shown enhanced NMDAR-mediated toxicity in cells expressing mutated Htt as well PLoS ONE | www.plosone.org 1 September 2011 | Volume 6 | Issue 9 | e24467