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: 6.34). 09/2009; 29(33):10371-86. DOI: 10.1523/JNEUROSCI.1592-09.2009
Source: PubMed


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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Available from: Carlos Cepeda, Oct 04, 2015
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    • "Thus, a recent targeted rescue study in a mouse model of HD provided evidence that it is the combination of mutant Huntingtin in cortical neurons and in MSNs that accounts for MSN degeneration and striatal dysfunction (Wang et al., 2014). HD might therefore initially involve deficits in neurons synapsing onto MSNs (Cummings et al., 2009; Thomas et al., 2011), but the degeneration is then most pronounced in MSNs (Cowan et al., 2008). In other words, mutant Huntingtin might not be sufficient to cause loss of excitation and degeneration of MSNs in HD, but combined with loss of critical excitatory inputs by cortical neurons, it then causes degeneration in MSNs (Figure 2). "
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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 · 15.05 Impact Factor
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    • "However, this autopsy data should be interpreted with caution. As mutant htt alters electrophysiological properties of cortical neurons (Cummings et al., 2009) and neuronal activity regulates Bdnf gene expression (Aid et al., 2007), we should not exclude the possibility that the observed reduction in cortical Bdnf mRNA levels may be secondary to neurodegeneration. "
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    ABSTRACT: The striatum, a major component of the basal ganglia, performs multiple functions including control of movement, reward, and addiction. Dysfunction and death of striatal neurons are the main causes for the motor disorders associated with Huntington's disease (HD). Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is among factors that promote survival and proper function of this neuronal population. Here, we review recent studies showing that BDNF determines the size of the striatum by supporting survival of the immature striatal neurons at their origin, promotes maturation of striatal neurons, and facilitates establishment of striatal connections during brain development. We also examine the role of BDNF in maintaining proper function of the striatum during adulthood, summarize the mechanisms that lead to a deficiency in BDNF signaling and subsequently striatal degeneration in HD, and highlight a potential role of BDNF as a therapeutic target for HD treatment.
    Frontiers in Cellular Neuroscience 08/2014; 8:254. DOI:10.3389/fncel.2014.00254 · 4.29 Impact Factor
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    • "Alterations in dendritic spine survival and density in cortical neurons characteristic of mouse model of HD accompany early symptoms of HD (41). There is also evidence that altered excitatory and inhibitory inputs to pyramidal neurons in the cortex are characteristics of disease progression in various mouse models of HD, which points to early signs of synaptic dysregulation involving glutamate and GABA signaling (42, 43). "
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    ABSTRACT: Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, HETzQ175, and HOMzQ175 genotypes in response to the odor of almond. The study was designed to see how alterations in the huntingtin gene in a mouse model of Huntington's disease would affect the perception and processing of almond odor, an evolutionarily conserved stimulus with high emotional and motivational valence. Moreover, the mice in this study were "odor naïve," i.e., never having smelled almond or any nuts. Using a segmented, annotated MRI atlas of the mouse and computational analysis, 17 out of 116 brain regions were identified as responding differently to almond odor across genotypes. These regions included the glomerulus of the olfactory bulb, forebrain cortex, anterior cingulate, subiculum, and dentate gyrus of the hippocampus, and several areas of the hypothalamus. In many cases, these regions showed a gene-dose effect with HETzQ175 mice showing a reduction in brain activity from wild-type that is further reduced in HOMzQ175 mice. Conspicuously absent were any differences in brain activity in the caudate/putamen, thalamus, CA3, and CA1 of the hippocampus and much of the cortex. The glomerulus of the olfactory bulb in HOMzQ175 mice showed a reduced change in BOLD signal intensity in response to almond odor as compared to the other phenotypes suggesting a deficit in olfactory sensitivity.
    Frontiers in Neurology 06/2014; 5:94. DOI:10.3389/fneur.2014.00094
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