title: Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.
abstract: 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.
authors.affiliation: Department of Psychiatry, Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kolodziejczyk
authors.affiliation: 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.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D013788:Thalamus / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Channelrhodopsin stimulation; Coculture; Corticostriatal synapse; Electrophysiology; Extrasynaptic NMDAR; Huntington disease; Spiny projection neurons; Thalamostriatal synapse