Dopamine neuron dependent behaviorsmediated by glutamate cotransmission
Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.
Article and author information
National Institute on Drug Abuse (MH 087758)
- Stephen Rayport
National Institute on Drug Abuse (DA017978)
- Stephen Rayport
NARSAD (Young Investigator Award)
- Susana Mingote
National Institute of Mental Health (MH086404)
- Holly Moore
- Stephen Rayport
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, under protocols approved by the Institutional Animal Care and Use Committees of Columbia University (# AC-AAAB2862) and New York State Psychiatric Institute (# 1249). All surgery was performed under ketamine + xylazine anesthesia, and every effort was made to minimize suffering.
- Sacha B Nelson, Brandeis University, United States
- Received: April 6, 2017
- Accepted: July 6, 2017
- Accepted Manuscript published: July 13, 2017 (version 1)
- Version of Record published: September 14, 2017 (version 2)
© 2017, Mingote et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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