Abstract
Huntington's disease (HD) is a neurodegenerative condition characterized by severe neuronal loss in the cortex and striatum that leads to motor and behavioral deficits. Excitotoxicity is thought to be involved in HD and several studies have indicated that NMDA receptor (NMDAR) overactivation can play a role in the selective neuronal loss found in HD. Interestingly, a small subset of striatal neurons (less than 1% of the overall population) is found to be spared in post-mortem HD brains. These neurons are medium-sized aspiny interneurons that highly express the neuronal isoform of nitric oxide synthase (nNOS). Intriguingly, neurons expressing large amounts of nNOS [hereafter indicated as nNOS(+) neurons] show reduced vulnerability to NMDAR-mediated excitotoxicity. Mechanisms underlying this reduced vulnerability are still largely unknown and may shed some light on pathogenic mechanisms involved in HD. One untested possibility is that nNOS(+) neurons possess fewer or less functioning NMDARs. Employing single cell calcium imaging we challenged this hypothesis and found that cultured striatal nNOS(+) neurons show NMDAR-evoked responses that are identical to the ones observed in the overall population of neurons that express lower levels of nNOS [nNOS(−) neurons]. NMDAR-dependent deregulation of intraneuronal Ca2+ is known to generate high levels of reactive oxygen species of mitochondrial origin (mt-ROS), a crucial step in the excitotoxic cascade. With confocal imaging and dihydrorhodamine (DHR; a ROS-sensitive probe) we compared mt-ROS levels generated by NMDAR activation in nNOS(+) and (−) cultured striatal neurons. DHR experiments revealed that nNOS(+) neurons failed to produce significant amounts of mt-ROS in response to NMDA exposure, thereby providing a potential mechanism for their reduced vulnerability to excitotoxicity and decreased vulnerability in HD.
Highlights
Excitotoxicity is a major pathogenic component of several neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease (HD) (Choi, 2005; Lau and Tymianski, 2010; Spalloni et al, 2013)
DISCUSSION neuronal isoform of nitric oxide synthase (nNOS)(+) neurons are spared from NMDA receptor (NMDAR)-driven excitotoxicity, a phenomenon that has puzzled the field for many years (Beal et al, 1986; Koh and Choi, 1988; Kumar, 2004; El Ghazi et al, 2012)
NNOS(+) striatal neurons possess fully functional NMDARs and respond to receptor activation with [Ca2+]i rises that do not differ for amplitude and temporal dynamics to the ones observed in the overall population of nNOS(−) neurons
Summary
Excitotoxicity is a major pathogenic component of several neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease (HD) (Choi, 2005; Lau and Tymianski, 2010; Spalloni et al, 2013). Inheritance of the huntingtin (Htt) protein showing a pathogenic expansion of a glutamine stretch (polyQ repeats >35) (Macdonald et al, 1993) leads to massive cortical and striatal neuronal loss (Halliday et al, 1998; Cattaneo et al, 2005; Guo et al, 2012) Reasons for this sub-regional selectivity of the neurodegenerative process are not completely understood, several mechanisms have been proposed. A subpopulation of striatal neurons (accounting for less than 1% of the overall population) expresses high levels of the enzyme nicotinamide adenine dinucleotide phosphatediaphorase (NADPH-d) that is the neuronal isoform of nitric oxide synthase (nNOS) (Hope et al, 1991) These neurons expressing large amount of nNOS [hereafter called nNOS(+) neurons] are not affected by NMDAR-dependent toxicity and spared in the striatum of HD patients (Ferrante et al, 1985; Koh et al, 1986; Koh and Choi, 1988). We tested whether exposure to NMDA in striatal cultures generated different levels of mitochondrial ROS (mt-ROS) in nNOS(+) neurons compared to the overall population of nNOS(−) cells
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