Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition |
| |
Authors: | Madeleine V King Nisha Kurian Si Qin Nektaria Papadopoulou Ben HC Westerink Thomas I Cremers Mark P Epping-Jordan Emmanuel Le Poul David E Ray Kevin CF Fone David A Kendall Charles A Marsden Tyson V Sharp |
| |
Institution: | 1.School of Biomedical Sciences, University of Nottingham Medical School, Queen''s Medical Centre, Nottingham, UK;2.Department of Biomonitoring and Sensoring, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands;3.Brains On-Line BV, Groningen, The Netherlands;4.Addex Pharmaceuticals SA, Chemin des Aulx, Geneva, Switzerland |
| |
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. |
| |
Keywords: | VGLUT1 shRNA hippocampus glutamate learning memory |
|
|