Furthermore, selective sparing of SST positive neurons in bNOS knockout mice suggests that the presence of SST is essential for the survival of interneurons.

The presence of SST in the central and peripheral nervous system is associated with several physiological functions, which are attributed to different receptor subtypes, namely somatostatin receptor 1-5, which are members of G-protein coupled receptor family. All five SSTR subtypes display overlapping distribution in different parts of brain and importantly couple to Gi protein and inhibit cAMP in a pertussis toxin sensitive manner. SSTRs are involved in the regulation of ion channels; inhibition of Ca2+ and activation of K + channels involved in the release of several neurotransmitters and modulation of neurotransmission. These functional properties of SSTR subtypes can be further enhanced by interaction with members of their own family as well as other GPCRs, including dopamine and opioid receptors via heterodimerization. Widespread distribution of SSTRs in CNS is involved in various neurological diseases such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, epilepsy, HIV encephalitis, dementia and psychiatric disorders, including schizophrenia. These studies cumulatively suggest the critical and pivotal role of SSTR subtypes in neurodegenerative diseases. We recently observed that the knock-down of SSTR 1 and SSTR 5 using antisense oligonucleotides accelerated neuronal death upon NMDA treatment in cultured striatal neurons. Accordingly, in an attempt to elucidate the possible functions of SSTR1 and 5, the present study was undertaken to determine the expression of NMDARs, DARPP-32, calbindin, bNOS/SST and SSTRs in striatum of R6/2 and SSTR1/52/2mice. In addition, we also studied the downstream signaling cascades including calcineurin, calpain, PKC-a, ERK1/ 2, synapsin-IIa and enkephalin associated in the process of neurodegeneration in HD pathology as well as in experimental models of the disease.

In the present study, for the first time, we describe that the SSTR1/5 complex is a critical regulator of NMDARs, DARPP-32 and downstream signaling cascades normally seen in R6/2 transgenic mice. Importantly, this study revealed that SSTR1/52/2 mice mimic neuro-and biochemical changes of presymptomatic HD transgenic mice. The role of activated NMDARs in degeneration of medium spiny neurons in HD as well as in excitotoxicity is indisputable. Several previous studies have shown the activation of NMDAR subtypes in the brain of R6/2 transgenic mice. We sought to determine whether R6/2 and SSTR1/52/2 mice exhibit comparable cellular distribution pattern in NMDAR subunits and determined the expression levels of NR1, NR2A and NR2B using immunohistochemistry and Western blot analysis. As shown in Figure 3a, in wt mice brain NR1-like immunoreactivity in striatal neurons was confined to the cell membranes, as well as, intracellularly. Additionally, NR1-like immunoreactivity was also seen in nerve fibers. In comparison to wt, R6/2 mice brain displayed strong NR1 immunoreactivity that was restricted to cell membrane. Whether SSTR subtype regulates DARPP-32 phosphorylation is not known. Here we provide the evidence that in the absence of SSTR subtypes, DARPP-32 expression is decreased in striatum in a similar manner as seen in HD brain and/or HD transgenic mice. The loss of DARPP-32 like immunoreactivity in SSTR1/52/2 mice is not surprising; as previous studies have also shown that DARPP-322/2 mice resemble HD mice in dopamine signaling. Consistent with the existing notion that bNOS positive neurons are preserved in HD, the expression pattern and quantification of bNOS positive neurons in R6/2 mice as well as SSTR1/52/2 mice is comparable. Similar is the pattern of SST expression in both strains.