In line with previous observations, our results further strengthen the concept of selective preservation of medium-sized aspiny interneurons expressing SST/b-NOS. Furthermore, our previous studies have shown that blockade of SST using antisense oligonucleotide leads to the loss of bNOS/NADPH-d positive neurons upon QUIN/NMDA treatment. Taken together, these results support the notion that the presence of SST is likely responsible for the survival of aspiny interneurons in excitotoxicity. In HD, the activation of NMDAR is one of the leading causes of neuronal loss, in addition to the mutation in Htt.
Functional and physiological significance of NMDARs has recently been described in pathophysiology of HD and reported that the NMDAR antagonist, memantine, blocks the nuclear inclusion of mutated Htt seen in HD. Furthermore, recent studies have shown the distinct role of synaptic and extrasynaptic NMDARs in early and late onset of HD. NMDAR positive neurons are most vulnerable in HD as well as in various mouse models of excitotoxicity. Cumulatively, these studies indicate an increase NR1 and the loss of NR2B expression. However, studies for NR2A are controversial and such discrepancies may be due to the mouse strain used as a model. In the current study, an increased NR1 and NR2A expression, with the loss of NR2B immunoreactivity in both R6/2 and SSTR1/52/2 mice may be linked to the neurodegeneration of MSNs, which is attributed to an increased Ca2+ influx. Moreover, in SSTR1/52/2 mice, NR2A and NR2B immunoreactivity accumulates intracellularly while in R6/2 both receptors are well expressed at cell surface. In light of these results, we propose two different mechanisms for the role in NMDAR-mediated neurotoxicity. First, the membrane expression of NR2A and NR2B in HD transgenic mice allows receptor interaction at cell surface, which results in excitotoxicity. Consistent with the existing concept that NMDARs are functionally active in heteromeric complex, the increased cell surface expression of NR1 and NR2A in R6/2 might be involved in excitotoxicity through heterodimerization.
In the absence of SSTR subtypes, NMDAR trafficking might be impaired, leading to receptor accumulation intracellularly. Whether SSTR and NMDAR functionally interact with each other is not known and further studies are in progress to determine this. Studies are warranted to delineate the molecular mechanism for the intracellular accumulation of NMDAR in SSTR1/52/2 mice. Furthermore, the possibility of impaired mitochondrial function in these processes cannot be ruled out. The physiological response of cells upon the activation of SSTRs is receptor specific and can display multiple effects. SSTR2 is known to inhibit Ca2+ activated channels and increased neuronal Ca2+ is detrimental in excitotoxicity in vitro as well as in HD. Our results show increased expression of SSTR2 in the absence of SSTR1/5 and concomitantly in HD transgenic mice, suggesting a compensatory mechanism to inhibit Ca2+ due to enhanced excitatory input via the activation of NMDAR. In support, we have recently shown that SSTR2 and SSTR5 heterodimerize with significant changes in receptor pharmacological properties as well as enhanced signaling. Furthermore, SSTR1/52/2 mice exhibit increased expression of D2R in comparison to wt. Since SSTR5 and D2R functionally interact and exist in a heteromeric complex, the increased expression of D2R in SSTR1/52/2 mice supports the compensatory role in the absence of SSTR5 in vivo. Increased expression of NR1 and NR2A might be linked with the decreased expression of calcineurin and increased expression of calpain in R6/2 and SSTR1/52/2 mice. Calcineurin is involved in the phosphorylation of DARPP-32, which further regulates the cell survival pathways. Calcineurin knockout mice show the inhibition of motor functions, loss of synaptic plasticity, learning and memory. The loss of calcineurin expression in R6/2 and SSTR1/52/2 mice might correlate with the symptoms of HD. Furthermore, the loss of calcineurin and DARPP-32 expression can be correlated with the decreased expression of PKC-a. PKC-a plays a role in regulation of membrane associated signal transduction pathways mediated by Ca2+ homeostasis.