Hippocampal mossy fiber (Mf) synapses are viewed as conditional detonators, assisting CA3 cells in complex network functions. By analyzing mice deficient for GluK2 (GluR6), GluK3 (GluR7) and GluK5 (KA2) genes we show that kainate receptors (KARs) play a crucial role in the control of synaptic integration and spike transmission efficacy at Mf synapses. We dissected out the role of the different KAR functions at Mf synapses and we show that presynaptic and postsynaptic KARs concur to amplify unitary Mf synaptic inputs to trigger spike discharge within a wide range of frequencies (from 1 to 50 Hz). Moreover, KARs strongly favor spike transmission in response to patterns of presynaptic activity mimicking in vivo dentate granule cell activity. By amplifying spike transmission, KARs also facilitate the induction of associative long-term potentiation in CA3. Hence the actions of KARs as amplifiers of spike transmission contribute largely to the "conditional detonator" function of Mf synapses and are likely important for spatial information processing.

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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...

In hereditary neurodegenerative Huntington’s disease (HD), there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG) together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4Hz) power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD.

Study objectivesTo search for early abnormalities in electroencephalogram (EEG) during sleep which may precede motor symptoms in a transgenic mouse model of hereditary neurodegenerative Huntington’s disease (HD).DesignIn the R6/1 transgenic mouse model of HD, rhythmic brain activity in EEG recordings was monitored longitudinally and across vigilance states through the onset and progression of disease.Measurements and resultsMice with chronic electrode implants were recorded monthly over wake-sleep cycles (4 hours), beginning at 9–11 weeks (presymptomatic period) through 6–7 months (symptomatic period). Recording data revealed a unique β rhythm (20–35 Hz), present only in R6/1 transgenic mice, which evolves in close parallel with the disease. In addition, there was an unusual relationship between this β oscillation and vigilance states: while nearly absent during the active waking state, the β oscillation appeared with drowsiness and during slow wave sleep (SWS) and, interestingly, strengthened rather than dissipating when the brain returned to an activated state during rapid eye movement (REM) sleep.ConclusionsIn addition to providing a new in vivo biomarker and insight into Huntington's disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.

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