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, i.e., early versus 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.

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

“…However, CB 1 receptors located on glutamatergic terminals are strongly coupled to heterotrimeric G protein signaling (25) and, in fact, participate in the control of important neurobiological processes such as neuronal excitability (22), motor activity (26), feeding behavior (27), and anxiety (28). Our present findings support that this specific pool of CB 1 receptors should be considered a new key player in the excitotoxicity hypothesis of neural disease (29,30). On mechanistic grounds, it is very plausible that, upon intense activation of a glutamatergic projection, glutamate spillover out of the synapse would trigger in the target neuron the activation of the perisynaptic machinery of endocannabinoid generation (5), composed of type 1 metabotropic glutamate receptors (mostly mGluR5), G q/11 proteins, phospholipase C-β, and diacylglycerol lipase-α, thus producing the endocannabinoid 2-arachidonoylglycerol, which would engage presynaptic CB 1 receptors located on the glutamatergic terminal, thereby inhibiting excess excitatory transmission (5) and buffering the potential neurotoxic effects of extrasynaptic NMDA receptors in the postsynaptic neuron (31,32).…”

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

“…In HD, MSNs in the indirect pathway are relatively more vulnerable than those in the direct pathway, and were believed to be the first to be dysfunctional. Recent data surprisingly indicate that the MSNs originating the direct pathway are dysfunctional much earlier in the course of HD than previously described [19]. It remains an enigma as to whether there is something unique about the MSN that increases its vulnerability, or something that is lacking, which is neuroprotective in other neurons [1].…”

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

“…One such dysregulated gene, dopamine receptor D2 (DRD2 or D2), shows high expression levels in MSNs of the indirect pathway (striatopalladial) of the basal ganglion, which are among the earliest to die in HD (reviewed in ref. 7). Measuring the binding of the D2 ligand raclopride using PET scanning demonstrates reduced levels of DRD2 in the basal ganglia at, or even before, the onset of overt disease (8,9).…”