Article

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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    • "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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    • "To fully assess the pattern of the vasculature or arteries, the ROIs were sized 600 × 450 and 900 × 400 μm 2 for CoIV-stained and αSMA-stained sections, respectively. According to a mouse brain atlas (Paxinos and Franklin, 2004), these two ROIs are located in the somatosensory cortex and dorsocentral striatum, respectively (approximately bregma 0.5 mm, lateral 2.2 mm, and depth 1.2 mm, and bregma 0.5 mm, lateral 1.8 mm, and depth 1.8 mm, respectively ), and were chosen as areas for the cortical and subcortical tissues in the R6/2 mouse brain (Cummings et al., 2009; Zacharoff et al., 2012), respectively. For testing permeability using Evans Blue (EB), HD and WT mice of 12 weeks were intravenously injected with EB dye (4%, 4 ml/kg), and sacrificed 2 h post injection to harvest the brain. "
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    • "se neuronal circuits is central to the development of motor and cog - nitive deficits characteristic of Huntington ' s disease ( Cepeda et al . , 2007 ) . In vitro studies in R6 / 2 mouse brain slices have also iden - tified hyperexcitability in both striatal medium spiny neurons ( Klapstein et al . , 2001 ) and within cortical pyramidal neurons ( Cummings et al . , 2009 ) . Increased neuronal excitability may result from the loss of inhibition regulating striatal and cortical neurons that may include fast spiking parvalbumin interneurons which are known to generate gamma oscillations ( Bracci et al . , 2003 ) . Alternatively , hyperexcitability and gamma oscillations in R6 / 2 mice may be a result of t"
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