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Impaired Fear Extinction Recall in Serotonin Transporter Knockout Rats Is Transiently Alleviated during Adolescence

1
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands
2
Department of Pharmacological and Biomolecular Sciences, Universita’ degli Studi di Milano, 20133 Milan, Italy
3
Department of Clinical Genomics, Mayp Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
Brain Sci. 2019, 9(5), 118; https://doi.org/10.3390/brainsci9050118
Received: 27 March 2019 / Revised: 21 May 2019 / Accepted: 21 May 2019 / Published: 22 May 2019
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Abstract

Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we tested wildtype and serotonin transporter knockout (5-HTT−/−) rats of preadolescent, adolescent, and adult age for cued fear extinction and extinction recall. To analyze neural circuit function, we quantified inhibitory synaptic contacts and, through RT-PCR, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), and NDMA receptor subunits, in the medial prefrontal cortex (mPFC) and amygdala. Remarkably, the impaired recall of conditioned fear that characterizes preadolescent and adult 5-HTT−/− rats was transiently normalized during adolescence. This did not relate to altered inhibitory neurotransmission, since mPFC inhibitory immunoreactivity was reduced in 5-HTT−/− rats across all ages and unaffected in the amygdala. Rather, since mPFC (but not amygdala) c-Fos expression and NMDA receptor subunit 1 expression were reduced in 5-HTT−/− rats during adolescence, and since PFC c-Fos correlated negatively with fear extinction recall, the temporary normalization of fear extinction during adolescence could relate to altered plasticity in the developing mPFC. View Full-Text
Keywords: serotonin transporter; rat; fear extinction; medial prefrontal cortex; NMDA; BDNF; adolescence; age serotonin transporter; rat; fear extinction; medial prefrontal cortex; NMDA; BDNF; adolescence; age
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Schipper, P.; Brivio, P.; de Leest, D.; Madder, L.; Asrar, B.; Rebuglio, F.; Verheij, M.M.M.; Kozicz, T.; Riva, M.A.; Calabrese, F.; Henckens, M.J.A.G.; Homberg, J.R. Impaired Fear Extinction Recall in Serotonin Transporter Knockout Rats Is Transiently Alleviated during Adolescence. Brain Sci. 2019, 9, 118.

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