Differential Electrophysiological Changes in Striatal Output Neurons in Huntington's Disease

Abstract

There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptorexpressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for either DA D1 or D2 receptors to identify neurons. In early symptomatic YAC128 and BACHD mice, glutamate transmission was increased in both D1 and D2 MSSNs, but in different ways. D1 cells displayed increased sEPSC frequencies and decreased paired-pulse ratios (PPRs) while D2 cells displayed larger evoked glutamate currents but no change in sEPSC frequencies or PPRs. D1 receptor modulation of sEPSCs was absent in D1-YAC128 cells at the early symptomatic stage but was restored by treating the slices with tetrabenazine. In contrast, in fully symptomatic YAC128 mice, glutamate transmission was decreased specifically in D1 cells, and D1 receptor modulation was normal in D1-YAC128 cells. Behaviorally, early symptomatic mice showed increased stereotypies that were decreased by tetrabenazine treatment. Together, these studies support differential imbalances in glutamate and DA transmission in direct and indirect pathway MSSNs. Stereotypic behavior at an early stage could be explained by increased glutamate activity and DA tone in direct pathway neurons, whereas hypokinesia at later stages could result from reduced input onto these neurons.

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.…”

“…The increase in excitatory transmission in the striatum observed here and in other rodent models of HD has been postulated to have excitotoxic effects and induce aberrant synaptic remodeling that could play an important role in the changes in striatal function and motor behavior observed in older HD mice (8,14). Furthermore, the reduced excitatory synaptic transmission observed in 5-mo-old YAC128 mice (Fig.…”

“…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.…”

Interplay between periodic stimulation and GABAergic inhibition in striatal network oscillations

“…Dysfunction of neural pathways between cortex and the BG circuitry is linked to many brain disorders, such as Parkinson's disease (PD), L-DOPA-induced dyskinesia, Tourette's syndrome, impulse control disorders, pathological gambling and Huntington's disease [9][10][11][12][13][14][15][16][17]. The striatum is the largest and main input a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 nucleus of the BG, receiving glutamatergic inputs from all cortical areas and thalamus [18][19][20][21][22].…”