title: Lentiviral delivery of a vesicular glutamate transporter 1 (VGLUT1)-targeting short hairpin RNA vector into the mouse hippocampus impairs cognition.
abstract: Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Madeleine V
authors.initials: MV
authors.lastname: King
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Nisha
authors.initials: N
authors.lastname: Kurian
authors.affiliation: 1] Department of Biomonitoring and Sensoring, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands [2] Brains On-Line BV, Groningen, The Netherlands.
authors.forename: Si
authors.initials: S
authors.lastname: Qin
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Nektaria
authors.initials: N
authors.lastname: Papadopoulou
authors.affiliation: 1] Department of Biomonitoring and Sensoring, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands [2] Brains On-Line BV, Groningen, The Netherlands.
authors.forename: Ben H C
authors.initials: BH
authors.lastname: Westerink
authors.affiliation: 1] Department of Biomonitoring and Sensoring, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands [2] Brains On-Line BV, Groningen, The Netherlands.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Cremers
authors.affiliation: Addex Pharmaceuticals SA, Chemin des Aulx, Geneva, Switzerland.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Epping-Jordan
authors.affiliation: Addex Pharmaceuticals SA, Chemin des Aulx, Geneva, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Ray
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Kevin C F
authors.initials: KC
authors.lastname: Fone
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Marsden
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Tyson V
authors.initials: TV
authors.lastname: Sharp
mesh_terms: D000818:Animals; D002460:Cell Line; D003072:Cognition Disorders / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006624:Hippocampus / Q000473:pathology*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D050598:Vesicular Glutamate Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1
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