Cortical circuit alterations precede motor impairments in Huntington’s disease mice.

Cortical circuit alterations precede motor impairments in Huntington’s disease mice.

Publication date: Apr 29, 2019

Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.

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Burgold, J., Schulz-Trieglaff, E.K., Voelkl, K., Guti’errez-‘Angel, S., Bader, J.M., Hosp, F., Mann, M., Arzberger, T., Klein, R., Liebscher, S., and , Dudanova. Cortical circuit alterations precede motor impairments in Huntington’s disease mice. 06460. 2019 Sci Rep (9):1.

Concepts Keywords
Autopsy Photon calcium imaging
Cortex Proteomics
Cortical Neuron
Downregulation Neocortex
Histological Primary motor cortex
Huntington Anatomy
Layer 2 Neuroscience
Mice Branches of biology
Movement Disorder Cerebral cortex
Neocortex
Neurons
Photon
Primary Motor Cortex
Pyramidal Cells
Sci
Striatum
Synaptic
Time Resolved
Transgenic
Vivo
Wildtype

Semantics

Type Source Name
pathway BSID Reproduction
gene UNIPROT FASTK
gene UNIPROT TSC1
gene UNIPROT TSC2
gene UNIPROT TANK
gene UNIPROT PROC
disease MESH Atrophy
gene UNIPROT HNF4A
disease DOID Mody
disease MESH Mody
gene UNIPROT BRD2
gene UNIPROT CAMK2B
disease MESH Huntington disease
disease DOID Huntington disease
gene UNIPROT MBNL1
gene UNIPROT DUOXA1
gene UNIPROT UBXN11
gene UNIPROT SNAP25
gene UNIPROT STUB1
drug DRUGBANK Ascorbic acid
drug DRUGBANK Metformin
gene UNIPROT CEL
disease MESH multiple
disease MESH cognitive decline
disease MESH neurodegenerative disorder
gene UNIPROT SAR1A
gene UNIPROT ZFYVE9
drug DRUGBANK Coenzyme M
drug DRUGBANK Isoxaflutole
gene UNIPROT LARGE1
disease MESH defects
drug DRUGBANK Calcium
disease MESH movement disorder
drug DRUGBANK Edetic Acid
drug DRUGBANK Tromethamine
gene UNIPROT FLNB
gene UNIPROT SEC14L2
gene UNIPROT USO1
gene UNIPROT NXF1
drug DRUGBANK Ethanol
gene UNIPROT REG1A
gene UNIPROT TCOF1
gene UNIPROT SP8
gene UNIPROT SLC17A6
drug DRUGBANK L-Lysine
drug DRUGBANK Glycine
drug DRUGBANK Human Serum Albumin
gene UNIPROT SLC35G1
drug DRUGBANK Formaldehyde
gene UNIPROT TSPO
gene UNIPROT CHRM3
drug DRUGBANK Aspartame
drug DRUGBANK Albendazole
disease MESH visual
drug DRUGBANK Molybdenum Cofactor
gene UNIPROT REST
gene UNIPROT DDX53
gene UNIPROT SGSM3
gene UNIPROT ARID1B
gene UNIPROT ARID3A
gene UNIPROT POC1A
gene UNIPROT TTL
drug DRUGBANK Tricyclazole
gene UNIPROT PI3
gene UNIPROT RAN
drug DRUGBANK Ranitidine
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
disease MESH virus titer
gene UNIPROT ABCC8
drug DRUGBANK Mannitol
drug DRUGBANK Dexamethasone
drug DRUGBANK Carprofen
drug DRUGBANK Xylazine
drug DRUGBANK Ketamine
gene UNIPROT KNTC1
gene UNIPROT TNFSF14
drug DRUGBANK Water
disease DOID CBA
gene UNIPROT ARNTL
gene UNIPROT PSD4
disease MESH tic
gene UNIPROT SYNM
gene UNIPROT FYN
gene UNIPROT SLC6A4
gene UNIPROT KCNK3
gene UNIPROT CTRL
gene UNIPROT RBFOX3
gene UNIPROT PSD
gene UNIPROT SLC32A1
gene UNIPROT PISD
gene UNIPROT FBXL15
gene UNIPROT SLC17A7
gene UNIPROT FLVCR1
disease MESH separation
drug DRUGBANK Pidolic Acid
disease DOID PCA
gene UNIPROT FBN1
gene UNIPROT ELK3
gene UNIPROT EPHB1
gene UNIPROT SLC6A2
gene UNIPROT TNFRSF11A
disease MESH death
gene UNIPROT ARID1A
gene UNIPROT CTBP1
drug DRUGBANK Isoflurane
gene UNIPROT THOP1
disease MESH posture
gene UNIPROT DYRK3
drug DRUGBANK Medical air
gene UNIPROT IK
gene UNIPROT B3GALNT1
gene UNIPROT OCA2
drug DRUGBANK Proline
disease MESH **p
gene UNIPROT GKN1
gene UNIPROT SYN1
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT NOVA2
disease MESH dyskinesia
disease MESH tremor
gene UNIPROT HTT
gene UNIPROT CNTN3
gene UNIPROT TNFSF13
gene UNIPROT COL9A3
gene UNIPROT ANP32B
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT COL9A2
gene UNIPROT SCN8A
gene UNIPROT MPG
pathway BSID Neurodegenerative Diseases
pathway BSID Signal Transduction
gene UNIPROT MAX
disease MESH Development
drug DRUGBANK Trestolone
gene UNIPROT MENT
pathway BSID Metabolism

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