Dopamine neuron dependent behaviorsmediated by glutamate cotransmission
Abstract
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
Author details
Funding
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.
Reviewing Editor
- Sacha B Nelson, Brandeis University, United States
Ethics
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.
Version history
- 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)
Copyright
© 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.
Metrics
-
- 3,758
- views
-
- 694
- downloads
-
- 45
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich virtual reality environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.
-
- Neuroscience
Behavioral and pharmaceutical interventions reverse defects associated with increased cerebellar long-term depression in a mouse model of Fragile X syndrome.