fg-9041 and Huntington-Disease

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

Topics: Acoustic Stimulation; Age Factors; Analysis of Variance; Animals; Animals, Genetically Modified; Behavior, Animal; Corpus Striatum; Discrimination, Psychological; Disease Models, Animal; Electric Stimulation; Electroencephalography; Excitatory Amino Acid Antagonists; GABA Antagonists; Genotype; Huntingtin Protein; Huntington Disease; Inhibition, Psychological; Longitudinal Studies; Male; Nerve Tissue Proteins; Neural Pathways; Neuropsychological Tests; Nuclear Proteins; Picrotoxin; Prefrontal Cortex; Psychomotor Performance; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex, Startle; Synaptic Membranes; Trinucleotide Repeat Expansion

The striatum is critically important in motor, cognitive and emotional functions, as highlighted in neurological disorders such as Huntington's disease (HD) where these functions are compromised. The R6/2 mouse model of HD shows progressive motor and cognitive impairments and alterations in striatal dopamine and glutamate release. To determine whether or not dopamine-dependent neuronal plasticity is also altered in the dorsolateral striatum of R6/2 mice, we compared long term potentiation (LTP) and long term depression (LTD) in striatal slices from R6/2 mice with that seen in slices from wild type (WT) mice. In adult WT mice (aged 8-19 weeks), frequency-dependent bidirectional plasticity was observed. High frequency stimulation (four 0.5 s trains at 100 Hz, inter-train interval 10 s) induced LTP (134+/-5% of baseline), while low frequency stimulation (4 Hz for 15 min) induced LTD (80+/-5% of baseline). LTP and LTD were significantly blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (to 93+/-6% and 103+/-8% of baseline respectively), indicating that they are both dependent on NMDA glutamate receptor activation. LTP was significantly blocked by the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (98+/-8% of baseline), indicating that LTP is dependent on activation of dopamine D(1)-type receptors, whereas LTD was not significantly different (90+/-7%). In adult R6/2 mice (aged 8-19 weeks), LTP was significantly reduced (to 110+/-4% of baseline), while LTD was not significantly different from that seen in WT mice (85+/-6%). These data show that R6/2 mice have impaired dopamine-dependent neuronal plasticity in the striatum. As dopamine-dependent plasticity is a proposed model of striatum-based motor and cognitive functions, this impairment could contribute to deficits seen in R6/2 mice.

Topics: Animals; Benzazepines; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Radiation; Electric Stimulation; Excitatory Amino Acid Antagonists; Huntingtin Protein; Huntington Disease; Long-Term Potentiation; Mice; Mice, Transgenic; Nerve Tissue Proteins; Nuclear Proteins; Quinoxalines; Time Factors