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 a selective focus on 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.
Bibliographical noteFunding Information:
We thank Shannon Wolfman, Celia Gellman, Benjamin Inbar, Lauren Rosko, Karin Krueger, Leora Boussi and Sophia Tepler for technical assistance, Eugene Mosharov, Se Joon Choi, Hadassah Tamir, Benjamin Klein and David Hirschberg for advice, Norman Curthoys for glutaminase antisera, and Theresa Swayne in The Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, supported by NIH grant P30 CA013696. This work was supported by a NARSAD Young Investigator award (SM), DA017978 and MH087758 (SR) and MH086404 (SR, HM).
© Mingote et al.
- Amphetamine sensitization
- Latent inhibition
- Motivational salience
- Resilience model
ASJC Scopus subject areas
- Neuroscience (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Immunology and Microbiology (all)