Excitotoxicity has been implicated in HD [for review, see 8], and several in vitro and in vivo studies have strongly suggested that an increase in striatal excitotoxicity is responsible, at least in part, for the loss of neurons observed in this brain region in the YAC128 mouse [24–26,38,39]. Interestingly, besides their role in mediating excitotoxic cell death, it is now known that N-methyl-D-aspartate (NMDA) glutamate receptors can also regulate the mechanisms involved in the formation of intranuclear inclusions of mutant huntingtin depending on their localization (synaptic vs. extra-synaptic). Indeed, synaptic NMDA receptor activity can promote the formation of inclusions via a T complex-1 ring complex-dependent mechanism, thus rendering neurons more resistant to cell death , which is in agreement with the proposed neuroprotective role of inclusions in HD [24,31–33; for review, see 8]. On the other hand, stimulation of extra-synaptic NMDA receptors increases vulnerability to neuronal death by impairing the neuroprotective cyclic adenosine monophsophate response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1-alpha cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to SUMOylate and disaggregate mutant huntingtin, and thus decrease the inclusion load . In agreement, a specific increase in extra-synaptic NMDA receptor expression and function and a consequent decrease in nuclear CREB activation has been detected in the striatum of YAC128 mice. These changes are observed in the absence of dendritic morphological alterations and can be detected before the onset of the disease. Moreover, the dysregulation of this pathway is aggravated by an increase in the number of CAG repeats expressed (as assessed by comparing striatal neurons from YAC76 and YAC128 mice), and is dependent on caspase-6-mediated cleavage of mutant huntingtin, because caspase-6-resistant YAC128 striatal neurons do not show such alterations . According to these findings, long-term blockage of extra-synaptic NMDA receptor activity might have therapeutic benefits, whereas simultaneous blockage of synaptic and extra-synaptic NMDA receptor activity might prove to have long-term deleterious effects, as blockage of synaptic activity would eventually lead to neuronal death through an increase in intracellular soluble mutant huntingtin. Indeed, treatment of YAC128 mice from 2 to 4 months of age with a low dose (1 mg/kg) of memantine to block extra-synaptic (but not synaptic) NMDA receptor activity reversed the CREB signaling deficits as well as the early motor-learning deficits (i.e., induced a decrease in the number of falls when learning the rotarod test) . However, the authors did not analyze whether increasing inclusion formation through treatment with memantine could also delay the onset of the hyperkynesic phenotype in young YAC128 mice. Nevertheless, when treatment was continued until 12 months of age, YAC128 mice showed increased inclusion formation, reduced loss in striatal volume, and improved motor performance (as assessed by the rotarod test) . On the other hand, a high dose of memantine (30 mg/kg), which blocks both extra-synaptic and synaptic NMDA receptor activity, decreased the number of neuronal inclusions and worsened both the neuropathological (i.e., striatal volume) and behavioral (i.e., locomotor activity) outcomes . Taken together, these results further support the involvement of excitotoxicity in the neuropathology of HD, as extra-synaptic NMDA receptor activation results in the accumulation of N-terminal toxic fragments of mutant huntingtin. Furthermore, these findings support the neuroprotective role of intranuclear inclusions of mutant huntingtin and strongly suggest that maintenance of synaptic activity with abrogation of extra-synaptic activity can be of potential therapeutic relevance for HD. Indeed, two clinical trials that analyzed the potential therapeutic benefits of memantine treatment in HD patients have already been performed. In the first one, the effectiveness of this compound (up to 30 mg/day) with regard to retardation of the disease progression was examined in 27 patients in a 2-year multicenter trial. No motor decline was observed at the 12 and 24 months evaluations, strongly suggesting that memantine may be useful in the retardation of the progression of this neurodegenerative disorder . In agreement, in a subsequent pilot trial that included 12 patients, memantine (20 mg/day) significantly improved the motor symptoms (including chorea) although no effects on the cognitive, behavioral, functional, and independence ratings were detected .