Glutamate‐induced alterations in Ca²⁺ signaling are modulated by mitochondrial Ca²⁺ handling capacity in brain slices of R6/1 transgenic mice

Abstract

Huntington's disease is a neurodegenerative disorder caused by an expansion of CAGs repeats and characterized by alterations in mitochondrial functions. Although changes in Ca(2+) handling have been suggested, the mechanisms involved are not completely understood. The aim of this study was to investigate the possible alterations in Ca(2+) handling capacity and the relationship with mitochondrial dysfunction evaluated by NAD(P)H fluorescence, reactive oxygen species levels, mitochondrial membrane potential (DeltaPsi(m)) measurements and respiration in whole brain slices from R6/1 mice of different ages, evaluated in situ by real-time real-space microscopy. We show that the cortex and striatum of the 9-month-old R6/1 transgenic mice present a significant sustained increase in cytosolic Ca(2+) induced by glutamate (Glu). This difference in Glu response was partially reduced in R6/1 when in the absence of extracellular Ca(2+), indicating that N-methyl-D-aspartate receptors participation in this response is more important in transgenic mice. In addition, Glu also lead to a decrease in NAD(P)H fluorescence, a loss in DeltaPsi(m) and a further increase in respiration, which may have evoked a decrease in mitochondrial Ca(2+) Ca(2+)(m) uptake capacity. Taken together, these results show that alterations in Ca(2+) homeostasis in transgenic mice are associated with a decrease in Ca(2+)(m) uptake mechanism with a diminished Ca(2+) handling ability that ultimately causes dysfunctions and worsening of the neurodegenerative and the disease processes.

Glutamate induces autophagy via the two-pore channels in neural cells

“…It was demonstrated that hyperammonemia can increase the autophagy markers such as beclin-1, LC3II and p62 and contributes to muscle loss in sarcopenia with cirrhosis condition [40]. By contrast, a high concentration of glutamate leads progressively to cell death by apoptosis or other death mechanisms [41, 42]. Indeed, overstimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate can produce massive Ca 2+ entry, which is taken up by mitochondria and leads to excitotoxicity [43].…”

Modeling Pathogenesis of Huntington’s Disease with Inducible Neuroprogenitor Cells

“…Several lines of investigation have suggested that multiple mechanisms may underlie the neurotoxic effect of mutant Htt. These include oxidative stress (Stack et al, 2008), excitotoxicity (Graham et al, 2009), impaired mitochondrial integrity (Wang et al, 2009) and energy metabolism (Beal, 2000), dysregulation of calcium homeostasis (Rosenstock et al, 2010) and aberrant activation of transglutaminase (Jeitner et al, 2009), abnormal protein-protein interactions (Li et al, 2007; McGuire et al, 2006), impaired ubiquitin-proteasome system (UPS) (Seo et al, 2004; Wang et al, 2008), and transcriptional dysregulation and altered gene expression (Benn et al, 2008). Although each of these hypotheses is supported by evidence, often the results observed in one HD model cannot be replicated in another HD model system.…”

Opposite Roles of NMDA Receptors in Relapsing and Primary Progressive Multiple Sclerosis

“…In agreement with this conclusion, results of a recent placebo-controlled clinical trial showed that MS patients treated with the NMDAR antagonist memantine experienced reversible neurological impairment [63]. On the other hand, it has been convincingly established that excessive synaptic signaling through NMDARs causes excitotoxic neuronal damage by altering mitochondrial activity [64]–[66] and in fact mitochondrial function is severely compromised in progressive MS [67]–[69].…”