In Huntington’s disease (HD), mHtt expression results in altered corticostriatal synaptic function by synergizing glutamatergic and dopaminergic signaling, which increases intracellular Ca2+ mobilization and leads to excitotoxicity. This model bypasses the cascade of molecular signaling pathways and illustrates the ‘end result’ of mHtt-mediated dysfunction of each pathway. Solid lines represent augmented function and dashed lines illustrate reduced function, respectively. Dopamine release from the substantia nigra pars compacta stimulates D1 receptors on direct pathway MSNs and augments N-methyl-d-aspartate (NMDA)-mediated (NR2A) glutamate activity. TBZ inhibits dopamine release and probably attenuates this response. Activation of D2 receptor-mediated inhibition of glutamate release from presynaptic terminals is reduced in HD. Similarly, mGluR2 feedback-inhibition of glutamate release is also altered. Recent evidence has revealed that synaptic NR2A NMDA receptor signaling is not disrupted in HD and is in fact prosurvival, although the role of altered D1 activity on NR2A activity has not been fully elucidated. Therefore, it is conceivable that D1 activity results in pathological changes to NR2A function. Binding of mHtt sensitizes InsP3R1 to InsP3, resulting in supernormal Ca2+ release from the ER upon mGluR5 activation. Elevated intracellular Ca2+ is also caused by altered VGCC function. Moreover, mHtt expression potentiates NR2B NMDA receptor-mediated responses and further increases Ca2+ levels. Dysfunction and reduced expression of GLT1 impedes glutamate uptake from the synaptic cleft. Huntexil® (NeruoSearch A/S, Denmark), a dopamine stabilizer and D2 modulator, demonstrated efficacy in human HD clinical trials. The mGluR2 agonist LY39268 and mGluR5 antagonist MPEP have shown promise in mouse models of HD. Low-dose MMT, which preferentially blocks NR2B activity, and ceftriaxone, which increases expression of GLT1, have also been successful in preclinical trials with HD mouse models. Taken together, mHtt results in a potentiated bombardment of glutamate-mediated excitotoxic cascades in MSNs.ER: Endoplasmic reticulum; GLT: Glutamate transporter; InsP3: Inositol (1,4,5)-triphosphate; InsP3R: Inositol (1,4,5)-triphosphate receptor; mGluR: Metabotropic glutamate receptor; mHtt: Mutant huntingtin; MMT: Memantine; MPEP: 2-methyl-6-(phenylethynyl)-pyridine; MSN: Medium spiny neuron; TBZ: Tetrabenazine; VGCC: Voltage-gated Ca2+.
