TY  - JOUR
A1  - Araragi, Naozumi
A1  - Mlinar, Boris
A1  - Baccini, Gilda
A1  - Gutknecht, Lise
A1  - Lesch, Klaus-Peter
A1  - Corradetti, Renato
T1  - Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis
JF  - Frontiers in Neuropharmacology
N2  - Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.
KW  - serotonin transporter
KW  - tryptophan hydroxylase-2
KW  - knockout
KW  - dorsal raphe nucleus
KW  - autoinhibition
KW  - 5-HT1A receptor
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97098
ER  - 
TY  - JOUR
A1  - Waider, Jonas
A1  - Popp, Sandy
A1  - Mlinar, Boris
A1  - Montalbano, Alberto
A1  - Bonfiglio, Francesco
A1  - Aboagye, Benjamin
A1  - Thuy, Elisabeth
A1  - Kern, Raphael
A1  - Thiel, Christopher
A1  - Araragi, Naozumi
A1  - Svirin, Evgeniy
A1  - Schmitt-Böhrer, Angelika G.
A1  - Corradetti, Renato
A1  - Lowry, Christopher A.
A1  - Lesch, Klaus-Peter
T1  - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity
JF  - Frontiers in Neuroscience
N2  - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
KW  - tryptophan hydroxylase 2
KW  - knockout
KW  - fear learning
KW  - extinction
KW  - long-term potentiation
KW  - hippocampus
KW  - immediate-early gene
KW  - serotonin deficiency
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077
SN  - 1662-453X
VL  - 13
IS  - 245
ER  -