Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington's Disease Transgenic Mice

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.

Modulation of striatal neuron activity by cyclic nucleotide signalling and phosphodiesterase inhibition

“…It is currently unclear to what extent the above mentioned decreases in markers of cAMP/cGMP and PDE signaling result from disease-induced MSN death versus alterations in striatal function induced by mutant huntingtin. In the case of nNOS, however, cell death is likely not a major factor contributing to decreased striatal nNOS mRNA levels as a selective sparing of somatostatin/NPY/nNOS expressing interneurons is consistently observed in postmortem tissue from HD patients and in animal models [72, 77–80]. …”

The role of the neuropeptide somatostatin on methamphetamine and glutamate-induced neurotoxicity in the striatum of mice

“…As a modulator of striatal activity and many of its transmitters primarily through inhibition, SST has the capability to play a pivotal role in the events following METH as implicated by our data. In the striatum it is synthesized and stored in the SST/NPY/nNOS interneuron, colocalizing with NPY and nitric oxide synthase (Rajput et al, 2011a). Although this particular interneuron comprises approximately 0.8-2% of the striatal neuronal population (Cicchetti et al, 2000; Tepper and Bolam, 2004), they are localized throughout the striatum (Allen et al, 2003).…”

“…We demonstrate here that OCT (SST analogue) had a mitigating influence on NO synthesis thus reducing the oxidant state caused by METH. OCT was chosen based on a number of criteria, first that it has the highest affinity for the SST receptors 2 and 5, which according to several receptor expression studies may be the predominant subtypes expressed within the rodent striatum (Allen et al, 2003; Galarraga et al, 2007; Rajput et al, 2011a, 2011b). Therefore, they would be the most plausible receptors to have an impact on METH-induced toxicity.…”

“…Neurochemical analysis of mice lacking the SST 1 or 5 receptor revealed that they shared many similarities to a transgenic Huntington's murine model (Rajput et al, 2011a). One such similarity was the critical loss of a large percentage of striatal projection neurons thus implicating SST signaling as playing a central role in the regulation of neurodegeneration.…”

Somatostatin 2a receptors are not expressed on functionally identified respiratory neurons in the ventral respiratory column of the rat

“…The functional significance of SST release from putative preBötC neurons is unclear. Transgenic animals that lack SST (Low et al, ) or SST receptors (Allen et al, ; Qiu et al, ; Rajput et al, ) are not associated with an obvious respiratory phenotype. However, exogenous SST powerfully inhibits central respiratory drive in vivo (Yamamoto et al, ; Chen et al, ; Burke et al, ; Pantaleo et al, ) and in vitro (Llona et al, ; Gray et al, ; Ramírez‐Jarquín et al, ).…”