CONICET | Buscador de Institutos y Recursos Humanos

The dorsal raphe nucleus (DR) controls forebrain serotonin (5-Hydroxytryptamine, 5-HT), regulating stress and emotional states. Moreover, dysregulation of DR 5-HT cells excitability has been linked to pathophysiology of affective disorders including depression and anxiety. DR neurons are regulated by excitatory and inhibitory drives mediated by a complex network of glutamate and GABA axons. A recently developed high-resolution imaging technique called Array Tomography (AT) allows for a quantitative analysis of molecular components of synapses and their spatial relationships in the same tissue volume, also providing a meaningful approach to unmask novel anatomical features of circuits within the CNS. We used AT to study relationships between glutamate and GABA axons within the rat DR by visualizing synaptic markers for glutamatergic (Vesicular Glutamate Transporter, VGLUT1-3; Postsynaptic Density Protein, PSD-95) and GABAergic (Glutamate Decarboxylase 65, GAD2) systems, jointly with synapsin I as a general marker for synapses, and Tryptophan Hydroxylase for 5-HT cells. Although 5-HT cells receive innervations from both VGLUT1-3-positive glutamate axons and GABAergic axons, a high proportion of these innervations were associated with non-5-HT cells. The analysis of associations between glutamate and GABA axonal boutons revealed organizing features of axo-axonic interactions, mostly unrelated to 5-HT cells, and consistent with the ultrastructure as determined by immunoelectron microscopy. This study reveals new synaptic features of DR circuitry that may underlie to a direct GABAergic presynaptic regulation of glutamate transmission, recently proposed as a novel target for pharmacotherapy of affective disorders.

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