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SummaryDopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA neurons do not signal to spiny projection neurons in the medial dStr, while they elicit ionotropic glutamate responses in the lateral dStr. The DA neurons mediating these excitatory signals are in the substantia nigra (SN). Thus, SN dopamine neurons engage different receptors in different postsynaptic neurons in different dStr subregions to convey strikingly different signals.

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. DOI: http://dx.doi.org/10.7554/eLife.27566.001, eLife digest A small cluster of neurons found in the midbrain use dopamine to send signals to neurons involved in many processes including motivation and attention. Drugs of abuse such as amphetamine co-opt motivation by increasing dopamine signaling. When used excessively, the drugs can engender delusional thinking, as is seen in schizophrenia. In contrast, the drugs used to treat schizophrenia block excess dopamine signaling. Recently it has been shown that dopamine neurons in the middle part of the midbrain release both dopamine and glutamate. The exact role of this dopamine neuron glutamate signaling has been difficult to find out. Previous experiments involved genetically modifying dopamine neurons so that they would not release glutamate. However, this affected how the neurons develop, making it difficult to discern the effects of glutamate signaling. Now, in genetically modified mice that have less glutaminase in their dopamine neurons than normal, Mingote et al. find that glutamate signaling is reduced just when dopamine neurons fire more rapidly. This did not change how dopamine neurons develop or how they use dopamine to signal. This reduction in dopamine neuron glutamate signaling affects two behaviors that are driven by the activity of dopamine neurons. First, it reduces the effects of a process called amphetamine sensitization, in which repeated doses of amphetamine increase dopamine neuron signaling so that events associated with drug use take up more attention than they normally would. Second, the modified mice were better able to ignore familiar, irrelevant sounds in their environment; the mice continued to pay less attention to a familiar sound, even when it was paired with a shock and came to predict an unpleasant event – a process known as potentiation of latent inhibition. The effects on both of these processes suggest that dopamine neuron glutamate signaling helps animals decide which features of their environment are most important. This result suggests a new way of treating schizophrenia. When humans take amphetamine repeatedly, which produces sensitization, they can develop psychosis, a principal symptom of schizophrenia. During a period of psychosis, thoughts and perceptions are disturbed, making it difficult to distinguish between relevant or irrelevant things in the environment. By reducing amphetamine sensitization and potentiating latent inhibition, blocking dopamine neuron glutamate signaling might help to treat the symptoms of schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.27566.002