Figure 1.

Diagrammatic summary of time- and regional-dependent changes in excitation and inhibition in mouse models of HD. The left panels show the basic simplified microcircuits in the cortex (top) and striatum (bottom). The middle panels show changes in excitation and inhibition in early HD for cortex and striatum and the right panels show changes in excitation and inhibition in late HD. The basic microcircuit for the cortex (left top panel) shows excitatory input to pyramidal neurons from external inputs (primarily thalamus), intracortical excitatory connections from other pyramidal neurons and inhibitory input from interneurons. In early HD (top middle panel) there is an increase in inhibitory input with little change in excitatory input to pyramidal neurons. As indicated in the text, if inhibitory input is blocked there is a release of excitation (Cummings et al., 2009). In late HD there is a marked decrease in inhibitory inputs to pyramidal neurons and a concomitant increase in excitation. The basic circuit for the striatum (left bottom panel) shows MSNs of the direct (D1) and indirect (D2) pathways, their excitatory inputs (from cortex and thalamus), their inhibitory inputs from striatal interneurons and DA inputs from SNc (blue). The arrows in the left panel indicate that DA effects on D1 MSNs are facilitating, increasing inputs while those on D2 MSNs are attenuating, decreasing inputs. In early HD the DA inputs to D1 MSNs increase both excitatory and inhibitory inputs via a presynaptic effect. In contrast there is a decrease in D2 receptor function on indirect pathway MSNs, but no net presynaptic change. An increase in evoked EPSCs occurs that is probably mediated postsynaptically. In late HD there is a decrease in excitation to both D1 and D2 MSNs which is probably due to a disconnection from excitatory synaptic inputs. There also is an increase in inhibitory input, but only to D2 MSNs. These effects are explained further in the text.