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

Abstract

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.single unit | local field potential | high γ-oscillation | operant learning | pre-motor-symptomatic R6/1 mice H untington disease (HD) is a progressive and inherited neurodegenerative disorder associated with selective degeneration of medium-sized spiny projection neurons in the striatum (1). Although the disease is well characterized by symptoms such as involuntary choreiform movements, dystonias, and rigidity, these motor symptoms have been found to be preceded by personality, mood, and cognitive disturbances (2). Some postmortem studies have also shown only limited signs of pathologic processes or cell loss in the brain despite substantial clinical evidence of HD (3), suggesting that neuronal-and, more precisely, synapticdysfunction, rather than cell death, may predominantly underlie early behavioral manifestations of the HD mutation.Studies of the effects of the mutant HD gene in several transgenic mouse models, including the R6 lines, have indeed shown changes in the membrane properties, biochemistry, and morphology of fragile striatal cells (4, 5), suggesting compromised functional integrity. They have also shown early and progressive alterations in synaptic plasticity in the corticostriatal pathway (6). These changes have been hypothesized to underlie early cognitive and behavioral deficits in transgenic mice (and patients with HD) by altering striatal information processing and transfer within basal ganglia loops.To verify this hypothesis, we recorded single-unit activity and local field potentials (LFPs) in the dorsal striatum and cortex, whereas behaviorally naive pre-motor-symptomatic R6/1 mice (7) (14-18 wk old) and age-matched WT littermates acquired an association between a nose-poke (NP) action and reward through operant learning. This procedural learning of an action-reward association is known to critically involve the striatum, a crucial site for the integration of the sensorimotor, limbic, and cognitive information required for the selecti...

Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels

“…In one study using R6/1 mice, the majority of striatal neurones exhibited high γ-oscillations, a form of high-frequency activation not normally seen in normal mice. Such oscillations are reported in Parkinson's disease patients undergoing dopamine supplementation and in rats treated with dopamine agonists [59,60]. Our finding that striatal dopamine release is greatly augmented in presymptomatic R6/1-89Q mice supports the view that enhanced levels of striatal dopamine is a feature of early-stage disease and may underlie emergent properties such as high γ-oscillations.…”

“…In contrast, studies in the short-lived R6/2 mouse line suggested that dopamine release is actually reduced [24,27], though one study indicated a transient increase in the activity of TH in presymptomatic R6/2 mice [58]. Importantly, two recent studies provide indirect functional evidence that DA tone is enhanced in the striatum during early-stage disease [59,60]. In one study using R6/1 mice, the majority of striatal neurones exhibited high γ-oscillations, a form of high-frequency activation not normally seen in normal mice.…”

Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of β-catenin in dopamine neurons

“…Extensive evidence now indicates a role for the basal ganglia, in particular, the dorsal striatum, in learning and memory. Various motor learning tasks, such as chaining of motor sequences, visuomotor skill acquisition, instrumental lever-pushing, and serial reaction-time tests all involve the striatum (Cromwell and Berridge 1996;Doyon et al 1996;Reynolds et al 2001;Wickens et al 2003;Cayzac et al 2011;Ena et al 2011). As striatal learning is thought to depend on neuronal modification through alterations in neuronal ensemble activity and synaptic plasticity, we hypothesized that the lack of b-catenin in dopaminergic presynaptic terminals in the striatum may also alter the state of postsynaptic sites in striatal neurons.…”

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

“…Overall, these data demonstrate that Q97 CRE mice display deficits in motor coordination, suggesting that selective expression of mHtt during the developmental period partially recapitulates the motor deficits of HD. A number of studies have demonstrated defects in in vivo striatal spiking activity (14,15) and in vitro age-dependent alterations in different striatal cell types (14,16,17) in various HD mouse models. We sought to determine whether mHtt-associated developmental effects contribute to these electrophysiological alterations.…”