Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function

Abstract

Huntington's disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the progression of behavioral and physiological alterations, which had not been possible using classic neurotoxin models. Our groups have pioneered the use of transgenic HD mice to examine the excitotoxicity hypothesis of striatal neuronal dysfunction and degeneration, as well as alterations in excitation and inhibition in striatum and cerebral cortex. In this review, we focus on synaptic and receptor alterations of striatal medium-sized spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We demonstrate a complex series of alterations that are region-specific and time-dependent. In particular, many changes are bidirectional depending on the degree of disease progression, that is, early vs. late, and also on the region examined. Early synaptic dysfunction is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. The differential effects of altered glutamate release on MSNs originating the direct and indirect pathways is also elucidated, with the unexpected finding that cells of the direct striatal pathway are involved early in the course of the disease. In addition, we review evidence for early N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. The main findings indicate that HD treatments need to be designed according to the stage of disease progression and should consider regional differences.

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.

Figure 2

Model of mutant htt induced synaptic dysfunction in HD. Aberrant glutamate release from cortical and thalamic afferents stimulates postsynaptic and Ex-NMDARs on MSNs. Overactivation of Ex-NMDARs also may be facilitated by deficits in glutamate uptake by the transporter GLT-1 on astrocytes. The mutant htt protein affects multiple cellular processes such as Ca²⁺ homeostasis, mitochondria function, transcriptional regulation, protein-protein interactions and vesicular transport of proteins including neurotransmitter receptors. Mutant htt also affects group 1 metabotropic receptor signalling such that ER IP3 receptor activation and release of intracellular Ca²⁺ is increased. HD is also associated with decreased synaptic NMDAR stability and increased expression, function and signalling of Ex-NMDARs. Posttranslational modifications and altered protein interactions may facilitate synaptic NMDAR instability. For example, increased Ca²⁺ levels activating calcineurin may lead to increased activation of STEP in the PSD, which dephosphorylates the GluN2B Y1472 residue and mediates lateral diffusion to extrasynaptic sites. It is postulated that enhanced Ex-NMDAR stability may be mediated by increased binding to scaffolding proteins such as PSD-95. Ex-NMDAR stimulation leads to downregulation of pro-survival signalling such as CREB-mediated gene transcription, decreased mutant htt inclusion formation, and increased activation of pro-apoptotic signalling that facilitates further neuronal dysfunction and neurodegeneration.