title: Cellular resilience: 5-HT neurons in Tph2(-/-) mice retain normal firing behavior despite the lack of brain 5-HT.
abstract: Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.e. tryptophan hydroxylase-2 null mice (Tph2(-/-)) and their littermates, Tph2(+/-) and Tph2(+/+), by using whole-cell patch-clamp recordings in a brainstem slice preparation and single unit recording in anesthetized animals. We report that the active properties of dorsal raphe nucleus (DRN) 5-HT neurons in vivo (firing rate magnitude and variability; the presence of spike doublets) and in vitro (firing in response to depolarizing current pulses; action potential shape) as well as the resting membrane potential remained essentially unchanged across Tph2 genotypes. However, there were subtle differences in subthreshold properties, most notably, an approximately 25% higher input conductance in Tph2(-/-) mice compared with Tph2(+/-) and Tph2(+/+) littermates (p<0.0001). This difference may at least in part be a consequence of slightly bigger size of the DRN 5-HT neurons in Tph2(-/-) mice (approximately 10%, p<0.0001). Taken together, these findings show that 5-HT neurons acquire and maintain their signature firing properties independently of the presence of their principal neurotransmitter 5-HT, displaying an unexpected functional resilience to complete brain 5-HT deficiency.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Waider
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Barbieri
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Ozan
authors.initials: O
authors.lastname: Baytas
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Corradetti
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. Electronic address: bmlinar@unifi.it.
authors.forename: Boris
authors.initials: B
authors.lastname: Mlinar
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D065847:Dorsal Raphe Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D025802:Electric Capacitance; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D059326:Serotonergic Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques; D014365:Tryptophan Hydroxylase / Q000172:deficiency* / Q000235:genetics
chemical_list: D018377:Neurotransmitter Agents; D015221:Potassium Channels; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: Dorsal raphe; Electrophysiology; I(h); Membrane channels; Neuron firing; Tph2 null mice