Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin

Abstract

The neurodegenerative disorder Huntington disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, resulting in loss of striatal and cortical neurons. Although, the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here, we demonstrate the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt), and neuronal survival. Synaptic NMDA receptor (NMDAR) activity induces mtHtt inclusions via a TCP1 ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases vulnerability of mtHtt-neurons to cell death by impairing a neuroprotective CREB—PGC-1α cascade and increasing the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic YAC128 HD mice with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine also blocks synaptic NMDAR activity, decreases neuronal inclusions, and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in HD.

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…A low dose of memantine rescues neuropathological and behavioural phenotypes as well as electrophysiological abnormalities in models of HD. By contrast, high dose memantine worsens these symptoms 24,29 . Similarly, administration of a low memantine dose corrected defects in learning and memory tasks, such as performance in the Morris water maze and passive avoidance learning in a mouse model of AD 30 .…”

“…Similarly, Aβ-induced NMDAR dysfunction is mediated by Fyn, a tyrosine kinase that phosphorylates NR2B 21,22 and mediates its insertion into the plasma membrane 23 increasing the levels of NR2B on the cell surface. The activation of extrasynaptic NR2B-containing NMDARs also dephosphorylates and inhibits the CREB/ PGC1α signalling pathway, which makes cells expressing mHtt more susceptible to cell death 24 (Figure 1). Enhanced activation of extrasynaptic NMDAR further leads to excessive influx of Ca 2+ into the cell, which results in inappropriate activation of enzymes (i.e., calpains and other Ca 2+ -regulated enzymes) and mitochondrial dysfunction, and leads to apoptosis 18 .…”

“…The presence of Aβ oligomers, early intermediates in the Aβ aggregation pathway, has in turn been associated with increased activation of extrasynaptic NMDARs, which could cause a feedback loop leading to synaptic dysfunction 28 . However, the strongest evidence for the role of extrasynaptic NMDAR in cognitive impairment is the effectiveness of memantine, an NMDAR blocker (see below), in rodent models of HD and AD as well as in AD patients 24,[29][30][31] .…”

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…It is worth noting that NMDAR-dependent plasticity and transmission are altered in Huntington ' s disease transgenic mice much before the onset of motor defi cits. Two important recent papers provided strong arguments suggesting that the balance between synaptic and extrasynaptic NMDAR activity could be crucial in determining neuronal cell survival in Huntington ' s disease (Okamoto et al , 2009 ;Milnerwood et al , 2010 ). These studies were performed on YAC128 transgenic mice expressing mutant full-length human huntingtin (mtHTT) protein that contains a 128-length polyglutamine expansion.…”

“…The effi cacy of memantine to antagonize neurodegenerative pathways has been elegantly demonstrated in the context of Hungtinton ' s disease pathology in recent in vivo studies (Okamoto et al , 2009 ;Milnerwood et al , 2010 ). Given the link evidenced between NMDAR dysregulation and AD (see above), it seemed pertinent to evaluate the capacity of memantine to modulate A β release in in vitro and/or in vivo models.…”