Altered Cortical Glutamate Receptor Function in the R6/2 Model of Huntington's Disease

Abstract

Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice that express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N-methyl-D-aspartate (NMDA) currents and their Mg2+ sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic and wild-type (WT) mice at 21 days (before overt symptoms), 40 days (when symptoms begin), and 80 days (fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21- and 40-day-old R6/2 groups compared with WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of "flop" splice variants, whereas the majority of WT cells expressed the "flip" variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg2+ sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg2+. Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD.

Altered NMDA Receptor Trafficking in a Yeast Artificial Chromosome Transgenic Mouse Model of Huntington's Disease

“…The lack of mhtt potentiation of non-NMDA-type GluRs agrees with results from the R6/2 mouse model (Cepeda et al, 2001), supporting the idea of a selective functional interaction between NMDARs and mhtt. The absence of NMDAR current potentiation by mhtt in cortical neurons is consistent with a recent report in R6/2 mice (Andre et al, 2006) and may result in part from lower levels of NR2B relative to NR2A compared with MSNs (Li et al, 2003b), because previous work suggests that the NR2B subunit plays a role in mediating the functional effect of mhtt on NMDARs (Chen et al, 1999). A lower NR2B content in cortical neurons is supported by our results showing reduced IFN sensitivity compared with MSNs.…”

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

“…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).…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Given that the neurons at this age have already undergone substantial atrophy, it is difficult to distinguish whether these changes reflect changes in the expression or function of membrane ion channels, or whether those changes simply reflect the effect of small cell size on input resistance and membrane potential. However, it is worth noting that there is evidence for changes in active conductances expressed in pyramidal neurons, notably voltage-gated calcium currents, which show an increase in late symptomatic R6/2 animals [71].…”