W.B.G and B.H. contributed equally to this work.
Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning
Version of Record online: 12 NOV 2013
Copyright © 2013 Wiley Periodicals, Inc.
Volume 24, Issue 2, pages 204–213, February 2014
How to Cite
Glen, W. B., Horowitz, B., Carlson, G. C., Cannon, T. D., Talbot, K., Jentsch, J. D. and Lavin, A. (2014), Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning. Hippocampus, 24: 204–213. doi: 10.1002/hipo.22215
- Issue online: 21 JAN 2014
- Version of Record online: 12 NOV 2013
- Manuscript Accepted: 25 SEP 2013
- Manuscript Revised: 23 SEP 2013
- Manuscript Received: 10 MAY 2013
- NIMH. Grant Numbers: RL1 MH-83269, R01 MH-072880, P50 MH-064045
- NIDCR. Grant Number: UL1 DE-019580
- NINDS. Grant Number: PL1 NS-062410
- genetic model;
Genetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the Dtnbp1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in Dtnbp1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 μM). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia. © 2013 Wiley Periodicals, Inc.