Synaptic dysfunction and altered calcium homeostasis in the brain is common to many neurodegenerative disorders. Among these, Huntington disease (HD), which is inherited in an autosomal dominant fashion, can serve as a model for investigating these mechanisms. HD generally manifests in middle age as a disorder of movement, mood and cognition. An expanded polymorphic CAG repeat in the HIT gene results in progressive neurodegeneration that impacts striatal spiny projection neurons (SPNs) earliest and most severely. Striatal SPNs receive massive glutamatergic input from cortex and thalamus, and these excitatory synapses are a focus for early changes that can trigger aberrant downstream signaling to disrupt synaptic plasticity and lead to later degeneration. Mitochondria( dysfunction and altered intracellular calcium-induced calcium release and sequestration mechanisms add to the impairments in circuit function that may underlie prodromal cognitive and subtle motor deficits. These mechanisms and implications for developing disease-modifying therapy will be reviewed here. (C) 2016 Elsevier Inc. All rights reserved.