PT - JOURNAL ARTICLE AU - Ayesha Sengupta AU - Marco Bocchio AU - David M Bannerman AU - Trevor Sharp AU - Marco Capogna TI - Control of amygdala circuits by 5-HT neurons via 5-HT and glutamate co-transmission AID - 10.1523/JNEUROSCI.2238-16.2016 DP - 2017 Jan 13 TA - The Journal of Neuroscience PG - 2238-16 4099 - http://www.jneurosci.org/content/early/2017/01/20/JNEUROSCI.2238-16.2016.short 4100 - http://www.jneurosci.org/content/early/2017/01/20/JNEUROSCI.2238-16.2016.full AB - The serotonin (5-HT) system and the amygdala are key regulators of emotional behavior. Several lines of evidence suggest that 5-HT transmission in the amygdala is implicated in the susceptibility and drug treatment of mood disorders. Thus, elucidating the physiological mechanisms through which midbrain 5-HT neurons modulate amygdala circuits could be pivotal in understanding emotional regulation in health and disease. To shed light on these mechanisms, we performed patch-clamp recordings from basal amygdala (BA) neurons in brain slices from mice with channelrhodopsin (ChR2) genetically targeted to 5-HT neurons. Optical stimulation of 5-HT terminals at low frequencies (≤1Hz) evoked a short-latency excitation of BA interneurons (INs) that was depressed at higher frequencies. Pharmacological analysis revealed this effect was mediated by glutamate and not 5-HT since it was abolished by ionotropic glutamate receptor antagonists. Optical stimulation of 5-HT terminals at higher frequencies (10-20Hz) evoked both slow excitation and slow inhibition of INs. These effects were mediated by 5-HT since they were blocked by antagonists of 5-HT2A and 5-HT1A receptors, respectively. These fast glutamate- and slow 5-HT-mediated responses often co-existed in the same neuron. Interestingly, fast-spiking and non-fast-spiking INs displayed differential modulation by glutamate and 5-HT. Furthermore, optical stimulation of 5-HT terminals did not evoke glutamate release onto BA principal neurons (PNs), but inhibited these cells directly via activation of 5-HT1A receptors and indirectly via enhanced GABA release. Collectively, these findings suggest that 5-HT neurons exert a frequency-dependent, cell type-specific control over BA circuitry via 5-HT and glutamate co-release to inhibit the BA output.SIGNIFICANCE STATEMENTThe modulation of the amygdala by serotonin (5-HT) is important for emotional regulation and is implicated in the pathogenesis and treatment of affective disorders. Hence, it is essential to dissect the physiological mechanisms through which 5-HT neurons in the dorsal raphe nuclei modulate amygdala circuits. Here, we combined optogenetic, electrophysiological and pharmacological approaches to study the effects of activation of 5-HT axons in the basal nucleus (BA) of the amygdala. We found that 5-HT neurons co-release 5-HT and glutamate onto BA neurons in a cell type-specific and frequency-dependent manner. Thus, we suggest that theories on the contribution of 5-HT neurons to amygdala function should be revised to incorporate the concept of 5-HT/glutamate co-transmission.