Abnormal burst patterns of single neurons recorded in the substantia nigra reticulata of behaving 140 CAG Huntington's disease mice.

Huntington's disease (HD) is an inherited neurodegenerative disorder that causes neurological pathology in the basal ganglia and related circuitry. A key site of HD pathology is striatum, the principal basal ganglia input structure; striatal pathology likely changes basal ganglia output but no existing studies address this issue. In this report, we characterize single-neuron activity in the substantia nigra reticulata (SNr) of awake, freely behaving 140 CAG knock-in (KI) mice at 16-40 weeks. KI mice are a well characterized model of adult HD and are mildly symptomatic in this age range. As the primary basal ganglia output nucleus in rodents, the SNr receives direct innervation from striatum, as well as indirect influence via polysynaptic inputs. We analyzed 32 single neurons recorded from KI animals and 44 from wild-type (WT) controls. We found increased burst rates, without a concordant change in spike discharge rate, in KI animals relative to WTs. Furthermore, although metrics of burst structure, such as the inter-spike interval in bursts, do not differ between groups, burst rate increases with age in KI, but not WT, animals. Our findings suggest that altered basal ganglia output is a physiological feature of early HD pathology.

Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington's disease.

A behavior-related deficit in the release of ascorbate (AA), an antioxidant vitamin, occurs in the striatum of R6/2 mice expressing the human mutation for Huntington's disease (HD), a dominantly inherited condition characterized by striatal dysfunction. To determine the role of corticostriatal fibers in AA release, we combined slow-scan voltammetry with electrical stimulation of cortical afferents to measure evoked fluctuations in extracellular AA in wild-type (WT) and R6/2 striatum. Although cortical stimulation evoked a rapid increase in AA release in both groups, the R6/2 response had a significantly shorter duration and smaller magnitude than WT. To determine if corticostriatal dysfunction also underlies the behavior-related AA deficit in R6/2s, we measured striatal AA release in separate groups of mice treated with d-amphetamine (5 mg/kg), a psychomotor stimulant known to release AA from corticostriatal terminals independently of dopamine. Relative to WT, both AA release and behavioral activation were diminished in R6/2 mice. Collectively, our results show that the corticostriatal pathway is directly involved in AA release and that this system is dysfunctional in HD. Moreover, because AA release requires glutamate uptake, a failure of striatal AA release in HD is consistent with an overactive glutamate system and diminished glutamate transport, both of which are thought to be central to HD pathogenesis.