Age-Dependent Alterations of Corticostriatal Activity in the YAC128 Mouse Model of Huntington Disease

Abstract

Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits and is caused by an abnormal expansion of the CAG tract in the huntingtin (htt) gene. In humans, mutated htt induces a preferential loss of medium spiny neurons in the striatum and, to a lesser extent, a loss of cortical neurons as the disease progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation. We examined the activity of the corticostriatal pathway using a combination of electrophysiological and optical imaging approaches in brain slices and acutely dissociated neurons from the YAC128 mouse model of Huntington disease. The results demonstrated biphasic age-dependent changes in corticostriatal function. At 1 month, before the behavioral phenotype develops, synaptic currents and glutamate release were increased. At 7 and 12 months, after the development of the behavioral phenotype, evoked synaptic currents were reduced. Glutamate release was decreased by 7 months and was markedly reduced by 12 months. These age-dependent alterations in corticostriatal activity were paralleled by a decrease in dopamine D 2 receptor modulation of the presynaptic terminal. Together, these findings point to dynamic alterations at the corticostriatal pathway and emphasize that therapies directed toward preventing or alleviating symptoms need to be specifically designed depending on the stage of disease progression.

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

“…S3A; WT, n = 7; YAC128, n = 9; t test, P < 0.05), an effect that could also increase excitability of YAC128 SPNs at this age. Consistent with previous reports in other HD models (8,12,14), this early alteration of EPSCs was reversed in older animals. Thus, in SPNs recorded in slices from 5-to 6-mo-old YAC128 mice, there was a significant decrease in peak amplitudes of eEPSCs compared with SPNs from WT mice [ Fig.…”

“…Due to its pivotal importance in these domains, changes in striatal physiology can contribute to multiple neurological diseases, including Huntington's disease, Parkinson's disease, dystonia, and others. An increasing number of reports suggest that changes in striatal synaptic physiology, including changes at glutamatergic, dopaminergic, and cholinergic synapses, are evident beginning in the prediagnostic phase of HD (5,6,(8)(9)(10)(11)(12)(13)(14)(35)(36)(37). These changes may contribute to early motor, cognitive, and psychiatric abnormalities, and could set the stage for the extensive pathophysiological alterations appearing later in the striatum.…”

“…At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3)(4)(5)(6)(7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17,18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12)(13)(14) and could contribute to synaptic changes observed in later stages of HD (19,20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.…”

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

“…Although we are aware of no study in R6/1 mice, an in vitro intracellular recording study in R6/2 mice once again showed that their striatal MSNs were hyperexcitable at a presymptomatic age (6 wk), consistent with data from Rebec's group (22,23), and became hypoexcitable later at a symptomatic age (12 wk) (16). Another study of YAC128 transgenic mice also reported biphasic increase and subsequent decrease of synaptic transmission in the corticostriatal pathway with disease progression (24). Therefore, this age-related biphasic temporal evolution of basal ganglia physiology caused by mutant proteins might explain the discrepancy between the excitability observed in previous in vivo recording studies in presymptomatic R6/2 mice (6-9 wk) and our findings in older R6/1 mice (14-20 wk).…”