Abstract
BackgroundSelective 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 FindingsTo 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.ConclusionsThis 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.
Highlights
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]
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
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)
Summary
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]. The functional importance of NMDARs emerged from a study describing the role of NMDAR antagonist memantine to block the nuclear inclusion of Htt in yeast artificial chromosome (YAC) mice [19]. These data suggest that NMDARs play an important role in HD and may contribute to neuronal loss. 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). 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)
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