Modulatory synapses in the brain: new biological features and functions of dopaminergic and serotonergic synapses

Abstract

Diffuse modulatory systems, such as the dopaminergic and serotonergic systems, are essential in the brain for broadly regulating diverse neural functions, including motor control, reward processing, emotions, and mood. Despite their functional importance, the comprehensive biological features and functions of modulatory synapses in the central nervous system remain poorly understood. In this talk, we introduce novel biological principles and functions of serotonergic and dopaminergic synapses in the hippocampus and striatum, respectively. First, using electrophysiology, optogenetics, immunohistochemistry, and confocal imaging, we demonstrate that synaptic transmission from raphe nuclei di-synaptically influences neuronal activity in hippocampal CA1 neurons. Importantly, this raphe-driven synaptic transmission critically regulates hippocampal synaptic plasticity through VGLUT3-dependent glutamate co-transmission. Furthermore, this modulation is predominantly mediated by CCK-expressing interneurons in the hippocampus. In the second part of the talk, we present evidence indicating that dopaminergic presynaptic boutons in the striatum are primarily engulfed by microglia, but not astrocytes. Additionally, this microglia-dependent engulfment of dopaminergic boutons is dynamically regulated by the activation state of dopamine neurons and significantly affects the functional properties of dopamine synapses in the striatum. Together, these findings reveal previously unrecognized mechanisms by which modulatory synapses dynamically shape neural circuitry and function, offering potential insights into the pathophysiology of various neurological disorders.