title: Impaired development of cortico-striatal synaptic connectivity in a cell culture model of Huntington's disease.
abstract: Huntington's disease (HD) is a genetically inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein. This mutation results in progressive cell death that is particularly striking in the striatum. Recent evidence indicates that early HD is initially a disease of the synapse, in which subtle alterations in synaptic neurotransmission, particularly at the cortico-striatal (C-S) synapse, can be detected well in advance of cell death. Here, we used a cell culture model in which striatal neurons are co-cultured with cortical neurons, and monitored the development of C-S connectivity up to 21days in vitro (DIV) in cells cultured from either the YAC128 mouse model of HD or the background strain, FVB/N (wild-type; WT) mice. Our data demonstrate that while C-S connectivity in WT co-cultures develops rapidly and continuously from DIV 7 to 21, YAC128 C-S connectivity shows no significant growth from DIV 14 onward. Morphological and electrophysiological data suggest that a combination of pre- and postsynaptic mechanisms contribute to this effect, including a reduction in both the postsynaptic dendritic arborization and the size and replenishment rate of the presynaptic readily releasable pool of excitatory vesicles. Moreover, a chimeric culture strategy confirmed that the most robust impairment in C-S connectivity was only observed when mutant huntingtin was expressed both pre- and postsynaptically. In all, our data demonstrate a progressive HD synaptic phenotype in this co-culture system that may be exploited as a platform for identifying promising therapeutic strategies to prevent early HD-associated synaptopathy.
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Caodu
authors.initials: C
authors.lastname: Buren
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Smith-Dijak
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, 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 / Q000473:pathology / Q000503:physiopathology*; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003712:Dendrites / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D008822:Mice, Transgenic; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D013572:Synaptic Vesicles / Q000473:pathology / Q000502:physiology
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid
keywords: Corticostriatal co-culture; Dendritic arborization; Excitatory synapse; Glutamate vesicle pool replenishment; Huntington's disease; Inhibitory synapse; Screening tool