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Rodents and humans show an attenuation of fear extinction during adolescence, which coincides with the onset of several psychiatric disorders. Although the ethological relevance and the underlying mechanism are largely unknown, the suppression of fear extinction during adolescence is associated with a diminished plasticity in the glutamatergic neurons of the infralimbic medial prefrontal cortex, a brain region critical for fear extinction. Given the putative effect of synaptic inhibition on glutamatergic neuron activity, we studied whether gamma-aminobutyric acidergic neurons in the infralimbic medial prefrontal cortex are involved in the suppression of fear extinction during adolescence. We assessed membrane and synaptic properties in parvalbumin-positive interneurons (PVINs) and somatostatin-positive interneurons (SSTINs) in male preadolescent, adolescent, and adult mice. The effect of fear conditioning and extinction on PVIN-pyramidal neuron and SSTIN-pyramidal neuron synapses in male preadolescent, adolescent, and adult mice was evaluated using an optogenetic approach. The development of the membrane excitability of PVINs is delayed and reaches maturity only by adulthood, while the SSTIN membrane properties are developed early and remain stable during development from preadolescence to adulthood. Although the synaptic inhibition mediated by PVINs undergoes a protracted development, it does not exhibit a fear behavior–specific plasticity. However, the synaptic inhibition mediated by SSTINs undergoes an adolescence-specific enhancement, and this increased inhibition is suppressed by fear learning but is not restored by extinction training. This altered plasticity during adolescence overlapped with a reduction in calcium-permeable glutamate receptors in SSTINs. The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice. [ABSTRACT FROM AUTHOR]

Summary The medial habenula-interpeduncular nucleus (MHb-IPN) pathway, which connects the limbic forebrain to the midbrain, has recently been implicated in aversive behaviors. The MHb-IPN circuit is characterized by a unique topographical organization, an excitatory role of GABA, and a prominent co-release of neurotransmitters and neuropeptides. However, little is known about synaptic plasticity in this pathway. An application of a high-frequency stimulation resulted in a long-lasting potentiation of glutamate release in IPN neurons. Our experiments reveal that a Ca 2+ -permeable AMPA receptor (CPAR)-dependent release of GABA from IPN neurons and a retrograde activation of GABA B receptors on MHb terminals result in a long-lasting enhancement of glutamate release. Strikingly, adolescent IPN neurons lacked CPARs and exhibited an inability to undergo plasticity. In addition, fear conditioning suppressed an activity-dependent potentiation of MHb-IPN synapses, whereas fear extinction reversed this plasticity deficit, suggesting a role of the MHb-IPN synaptic plasticity in the regulation of aversive behaviors. [ABSTRACT FROM AUTHOR]

Summary: Experiences of severe trauma during childhood are thought to be risk factors for developing mental disorders, such as anxiety and mood disorders, later in life. Correspondingly, exposure of rodents to early-life stress has been shown to affect neuronal circuitry and emotional behavior in adulthood, indicating a significant impact of stress on brain development. One current hypothesis proposes that the developing central nervous system is more sensitive to environmental influences, such as stress, than the adult. To test this hypothesis, we compared long-lasting effects of systemic corticosterone (CORT) administrations in two distinct early developmental periods. Mice exposed to early-neonatal CORT treatment on postnatal days (PD) 2–4 exhibited strongly enhanced excitability of neurons of the basolateral nucleus of the amygdala (BLA) in early adolescence and displayed impaired extinction of contextually conditioned fear memory, a type of behavior in which the BLA plays an important role. Furthermore, gene-expression of NMDA receptor subunits as well as calcium-activated K+-channels was reduced in the amygdala. In contrast, exposure to the same CORT concentrations in a late-neonatal period (PD17–19) did not significantly affect BLA electrophysiology or extinction learning in adolescence. These results suggest age-dependent consequences of neonatal CORT exposure in amygdala neurons and provide evidence for a detrimental influence of early-neonatal stress on adolescent fear-memory processing. [ABSTRACT FROM AUTHOR]

Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL‐mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL‐mPFC pyramidal neurons plays a role in this development‐dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL‐mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL‐mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning‐induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL‐mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience‐dependent modulation of neuronal excitability. Our results suggest that the extinction‐specific modulation of excitability is impaired during adolescence. Fear learning suppresses excitability of infralimbic medial prefrontal cortical pyramidal neurons. Consistent with the suppression of fear extinction during adolescence, fear extinction training fails to restore infralimbic medial prefrontal cortical pyramidal neuron excitability in adolescent mice. [ABSTRACT FROM AUTHOR]