PMID- 26621114
OWN - NLM
STAT- MEDLINE
DCOM- 20161014
LR  - 20170103
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 86
DP  - 2016 Feb
TI  - Differential changes in thalamic and cortical excitatory synapses onto striatal 
      spiny projection neurons in a Huntington disease mouse model.
PG  - 62-74
LID - S0969-9961(15)30098-X [pii]
LID - 10.1016/j.nbd.2015.11.020 [doi]
AB  - Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat 
      expansion in the gene encoding huntingtin, predominantly affects the striatum, 
      especially the spiny projection neurons (SPN). The striatum receives excitatory 
      input from cortex and thalamus, and the role of the former has been well-studied 
      in HD. Here, we report that mutated huntingtin alters function of thalamostriatal 
      connections. We used a novel thalamostriatal (T-S) coculture and an established 
      corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ 
      background strain) mice, to investigate excitatory neurotransmission onto 
      striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory 
      postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; 
      however, both the frequency and amplitude were significantly reduced in YAC128 
      T-S coculture. Further investigation in T-S coculture showed similar excitatory 
      synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting 
      changes in total dendritic length or probability of release as possible 
      explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor 
      (NMDAR) current was similar, but extrasynaptic current, associated with cell 
      death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical 
      stimulation of cortical versus thalamic afferents and recording from striatal SPN 
      in brain slice, we found increased glutamate release probability and reduced 
      AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in 
      YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both 
      cortical and thalamic stimulation. We conclude that thalamic afferents to the 
      striatum are affected early, prior to an overt HD phenotype; however, changes in 
      NMDAR localization in SPN are independent of the source of glutamatergic input.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Kolodziejczyk, Karolina
AU  - Kolodziejczyk K
AD  - Department of Psychiatry, Brain Research Centre and Djavad Mowafaghian Centre for 
      Brain Health, University of British Columbia, Vancouver, British Columbia, 
      Canada.
FAU - Raymond, Lynn A
AU  - Raymond LA
AD  - Department of Psychiatry, Brain Research Centre and Djavad Mowafaghian Centre for 
      Brain Health, University of British Columbia, Vancouver, British Columbia, 
      Canada. Electronic address: Lynn.raymond@ubc.ca.
LA  - eng
GR  - MOP-12699/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151124
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Htt protein, mouse)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cerebral Cortex/metabolism/*physiopathology
MH  - Coculture Techniques
MH  - Corpus Striatum/metabolism/pathology/*physiopathology
MH  - Dendrites/pathology
MH  - Disease Models, Animal
MH  - *Excitatory Postsynaptic Potentials
MH  - Huntingtin Protein
MH  - Huntington Disease/genetics/pathology/*physiopathology
MH  - Mice
MH  - Nerve Tissue Proteins/genetics
MH  - Neural Pathways/metabolism/pathology/physiopathology
MH  - Neurons/metabolism/*physiology
MH  - Nuclear Proteins/genetics
MH  - Receptors, AMPA/physiology
MH  - Receptors, N-Methyl-D-Aspartate/physiology
MH  - Synapses/*physiology
MH  - Thalamus/metabolism/*physiopathology
OTO - NOTNLM
OT  - Channelrhodopsin stimulation
OT  - Coculture
OT  - Corticostriatal synapse
OT  - Electrophysiology
OT  - Extrasynaptic NMDAR
OT  - Huntington disease
OT  - Spiny projection neurons
OT  - Thalamostriatal synapse
EDAT- 2015/12/02 06:00
MHDA- 2016/10/16 06:00
CRDT- 2015/12/02 06:00
PHST- 2015/07/27 00:00 [received]
PHST- 2015/11/09 00:00 [revised]
PHST- 2015/11/23 00:00 [accepted]
PHST- 2015/12/02 06:00 [entrez]
PHST- 2015/12/02 06:00 [pubmed]
PHST- 2016/10/16 06:00 [medline]
AID - S0969-9961(15)30098-X [pii]
AID - 10.1016/j.nbd.2015.11.020 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2016 Feb;86:62-74. doi: 10.1016/j.nbd.2015.11.020. Epub 2015 Nov 
      24.