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
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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.
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    • "In CPNs from R6/2 mice we reported biphasic changes in IPSC frequency. At 21 days of age before overt behavioral symptoms develop IPSC frequencies were increased, whereas at 80 days, in fully symptomatic mice, they were reduced (Cummings et al. 2009). In the same study we found that CPNs from YAC128 and CAG140 mice at 12 mo displayed increased IPSC frequencies. "
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    ABSTRACT: The Q175 knock-in mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission using whole-cell patch clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice. Input resistance in MSNs from Q175(+/+) and Q175(+/-) mice was significantly increased compared to wildtype (WT) littermates beginning at 2 months. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175(+/+) and Q175(+/-) mice compared to WTs beginning at 7 months. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC/EPSC ratios were increased in MSNs from Q175(+/+) mice beginning at 2 months. Morphologically, significant decreases in spine density of MSNs from Q175(+/-) and Q175(+/+) mice occurred at 7 and 12 months. In CPNs, sIPSC frequencies and IPSC/EPSC ratios were significantly increased in Q175(+/-) mice compared to WTs at 12 months. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175(+/-) mice, indicating reduced cortical excitability. Copyright © 2014, Journal of Neurophysiology.
    Full-text · Article · Feb 2015 · Journal of Neurophysiology
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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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