TY - JOUR
T1 - Impaired fear extinction recall in serotonin transporter knockout rats is transiently alleviated during adolescence
AU - Schipper, Pieter
AU - Brivio, Paola
AU - Leest, David De
AU - Madder, Leonie
AU - Asrar, Beenish
AU - Rebuglio, Federica
AU - Verheij, Michel M.M.
AU - Kozicz, Tamas
AU - Riva, Marco A.
AU - Calabrese, Francesca
AU - Henckens, Marloes J.A.G.
AU - Homberg, Judith R.
N1 - Publisher Copyright:
© 2019 by the authors.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Adolescence
KW - Age
KW - BDNF
KW - Fear extinction
KW - Medial prefrontal cortex
KW - NMDA
KW - Rat
KW - Serotonin transporte
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U2 - 10.3390/brainsci9050118
DO - 10.3390/brainsci9050118
M3 - Article
AN - SCOPUS:85068432841
SN - 2076-3425
VL - 9
JO - Brain Sciences
JF - Brain Sciences
IS - 5
M1 - 118
ER -