Dataset Information

Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.

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.

SUBMITTER: Cummings DM

PROVIDER: S-EPMC2754238 | biostudies-other | 2009 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.

Cummings Damian M DM André Véronique M VM Uzgil Besim O BO Gee Steven M SM Fisher Yvette E YE Cepeda Carlos C Levine Michael S MS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090801 33

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 ...[more]

PMID: 19692612

Similar Datasets

Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by a trinucleotide expansion in the HTT gene, which is expressed throughout the brain and body, including the gut epithelium and enteric nervous system. Afflicted individuals suffer from progressive impairments in motor, psychiatric, and cognitive faculties, as well as peripheral deficits, including the alteration of the gut microbiome. However, studies characterizing the gut microbiome in HD have focused entirely on the bacterial component, while the fungal community (mycobiome) has been overlooked. The gut mycobiome has gained recognition for its role in host homeostasis and maintenance of the gut epithelial barrier. We aimed to characterize the gut mycobiome profile in HD using fecal samples collected from the R6/1 transgenic mouse model (and wild-type littermate controls) from 4 to 12 weeks of age, corresponding to presymptomatic through to early disease stages. Shotgun sequencing was performed on fecal DNA samples, followed by metagenomic analyses. The HD gut mycobiome beta diversity was significantly different from that of wild-type littermates at 12 weeks of age, while no genotype differences were observed at the earlier time points. Similarly, greater alpha diversity was observed in the HD mice by 12 weeks of age. Key taxa, including Malassezia restricta, Yarrowia lipolytica, and Aspergillus species, were identified as having a negative association with HD. Furthermore, integration of the bacterial and fungal data sets at 12 weeks of age identified negative correlations between the HD-associated fungal species and Lactobacillus reuteri. These findings provide new insights into gut microbiome alterations in HD and may help identify novel therapeutic targets. IMPORTANCE Huntington's disease (HD) is a fatal neurodegenerative disorder affecting both the mind and body. We have recently discovered that gut bacteria are disrupted in HD. The present study provides the first evidence of an altered gut fungal community (mycobiome) in HD. The genomes of many thousands of gut microbes were sequenced and used to assess "metagenomics" in particular the different types of fungal species in the HD versus control gut, in a mouse model. At an early disease stage, before the onset of symptoms, the overall gut mycobiome structure (array of fungi) in HD mice was distinct from that of their wild-type littermates. Alterations of multiple key fungi species were identified as being associated with the onset of disease symptoms, some of which showed strong correlations with the gut bacterial community. This study highlights the potential role of gut fungi in HD and may facilitate the development of novel therapeutic approaches.

Dataset Information

Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.

Publications

Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets