Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington's Disease

Mental Retardation Research Center, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 09/2009; 29(33):10371-86. DOI: 10.1523/JNEUROSCI.1592-09.2009
Source: PubMed

ABSTRACT Previously, we identified progressive alterations in spontaneous EPSCs and IPSCs in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons from these mice displayed a lower frequency of EPSCs, and a population of cells exhibited an increased frequency of IPSCs beginning at approximately 40 d, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD: the R6/2, the YAC128, and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency, and evoked EPSCs were larger in behaviorally phenotypic mice whereas spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABA(A) receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.

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    ABSTRACT: Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell-cell interaction model, we used BACHD/Emx1-Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction. Copyright © 2015 the authors 0270-6474/15/354440-12$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(10):4440-51. DOI:10.1523/JNEUROSCI.2812-14.2015 · 6.75 Impact Factor
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    ABSTRACT: Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(5):901-910. DOI:10.1016/j.neuron.2014.12.063 · 15.98 Impact Factor
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    ABSTRACT: We describe a fast activity-dependent homeostatic regulation of intrinsic excitability of identified neurons in mouse dorsal stria-tum, the striatal output neurons. It can be induced by brief bursts of activity, is expressed on a time scale of seconds, limits repetitive firing, and can convert regular firing patterns to irregular ones. We show it is due to progressive recruitment of the KCNQ2/3 chan-nels that generate the M current. This homeostatic mechanism is significantly reduced in striatal output neurons of the R6/2 trans-genic mouse model of Huntington's disease, at an age when the neurons are hyperactive in vivo and the mice begin to exhibit loco-motor impairment. Furthermore, it can be rescued by bath perfusion with retigabine, a KCNQ channel activator, and chronic treatment improves locomotor performance. Thus, M-current dysfunction may contribute to the hyperactivity and network dysregulation charac-teristic of this neurodegenerative disease, and KCNQ2/3 channel regulation may be a target for therapeutic intervention. M current | intrinsic excitability | Huntington's disease | KCNQ channels | homeostasis H untington's disease (HD) is a fatal inherited autosomal neurodegenerative disorder, with its primary symptoms be-ing progressive development of motor and cognitive dysfunction (1). The mutated gene, huntingtin (HTT), and its mutation, an expansion of the number of CAG repeats, were identified 20 y ago. However, the mechanism(s) underlying the pathological changes that culminate in the degeneration of striatal output neurons (SONs) remain unknown. Early animal models (2) generated a number of testable hypotheses, most notable being that the neurons degenerate because of a hyperactivity that leads to a build-up of excitotoxic molecules. However, more recent studies implicate alternative pathologies, such as altered tran-scriptional activity, calcium regulation and mitochondrial func-tion, or disruptions in normal neuronal patterns of activity (3) and show that neuronal dysfunction and behavioral and motor symptoms of HD precede neurodegeneration (2). These studies have been facilitated by access to transgenic mice models, in-cluding R6/1 and R6/2 mice, which express a truncated region of the mutant human HTT gene with expanded CAG repeats (4). In vitro recordings in both lines revealed that SONs are depolarized and have higher input resistances than do wild-type (WT) con-trols, at a stage where deficits in locomotor activity begin to be manifest (5–7). Furthermore, in vivo recordings indicate that at 5–9 wk of age, when the mice exhibit overt motor deficits, R6/2 SONs have higher firing rates and more regular discharge pat-terns compared with WT (8, 9). In contrast, neurodegeneration and death occur later (2). Hence, we asked whether cellular mechanisms that influence excitability might be altered in the early stages of HD and might serve as targets for alleviating associated behavioral symptoms. Hyperactivity and related changes in neuronal firing patterns could reflect alterations in synaptic transmission and its activity-dependent modifications or in intrinsic membrane properties governing neuronal excitability (10–12). The latter can also be modulated by activity (13) and have homeostatic roles (14). We describe here a fast activity-dependent homeostatic control of excitability (fADH) in SONs. In WT mice, fADH can be induced by brief trains of impulses and is expressed on a time scale of seconds. It modifies firing rate and timing of evoked spikes, converting regular firing patterns to irregular ones, with the latter mode resembling the accommodation attributed to voltage-and time-dependent activation of the M current mediated by KCNQ [or voltage-gated potassium channel (Kv) subfamily 7 or Kv7] channels (14). Indeed, increasing activation of KCNQ channels on successive trials underlies fADH. Strikingly, we found that fADH is reduced in R6/2 SONs, that two KCNQ activators (15, 16) rescued fADH in R6/2 SONs, thereby re-storing WT firing patterns, and that the locomotor signs of HD in the R6/2 mouse were ameliorated by chronic treatment with one of the activators.
    Proceedings of the National Academy of Sciences 02/2015; · 9.81 Impact Factor

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