Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• Dopamine neurons in the ventral tegmental area utilize glutamate as a cotransmitter.
• The precise behavioral function of this glutamate cotransmission remains incompletely understood.

Purpose of the Study:

• To investigate the behavioral significance of glutamate cotransmission from dopamine neurons.
• To selectively reduce glutamate cotransmission by targeting the glutaminase enzyme (Gls1) in dopamine neurons.

Main Methods:

• Generated mice with a conditional heterozygous reduction of Gls1 specifically in dopamine neurons (Slc6a3-driven).
• Assessed dopamine neuron survival, transmission, and behavioral responses including emotional/motor behaviors, amphetamine response, amphetamine sensitization, and latent inhibition.
• Compared these findings with global Gls1 heterozygotes and mice with broader forebrain glutamatergic neuron reductions (Emx1-driven).

Main Results:

• Dopamine neuron survival and transmission were unaffected by the targeted Gls1 reduction.
• Glutamate cotransmission was reduced at phasic firing frequencies.
• Amphetamine sensitization was decreased, and latent inhibition was potentiated in the targeted mice.
• These behavioral changes mirrored those in global Gls1 heterozygotes exhibiting schizophrenia resilience and were absent in mice with broad forebrain Gls1 reduction.

Conclusions:

• Reduced dopamine neuron glutamate cotransmission mediates key aspects of the schizophrenia resilience phenotype observed in Gls1 heterozygotes.
• Glutamate cotransmission from dopamine neurons plays a significant role in the attribution of motivational salience.