Faculty Bibliography

The onset of several neuropsychiatric disorders including anxiety disorders coincides with adolescence. Consistently, threat extinction, which plays a key role in the regulation of anxiety-related behaviors, is diminished during adolescence. Furthermore, this attenuated threat extinction during adolescence is associated with an altered synaptic plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for threat extinction. However, the mechanism underlying the altered plasticity in the IL-mPFC during adolescence is unclear. Given the purported role of vasoactive intestinal polypeptide expressing interneurons (VIPINs) in disinhibition and hence their potential to affect cortical plasticity, we examined whether VIPINs exhibit an adolescence-specific plasticity in the IL-mPFC. We observed an increase in GABAergic transmission and a decrease in excitability in VIPINs during adolescence. Male mice show a significantly higher VIPIN-pyramidal neuron GABAergic transmission compared with female mice. The observed increase in GABAergic transmission and a decrease in membrane excitability in VIPINs during adolescence could play a role in the altered plasticity in the adolescent IL-mPFC. Furthermore, the suppression of VIPIN-mediated GABAergic transmission in females might be relevant to sex differences in anxiety disorders.

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS:The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice.

The medial habenula-interpeduncular nucleus (MHb-IPN) pathway has recently been implicated in the suppression of fear memory. A notable feature of this pathway is the corelease of neurotransmitters and neuropeptides from MHb neurons. Our studies in mice reveal that an activation of substance P-positive dorsomedial habenula (dMHb) neurons results in simultaneous release of glutamate and glycine in the lateral interpeduncular nucleus (LIPN). This glycine receptor activity inhibits an activity-dependent long-lasting potentiation of glutamatergic synapses in LIPN neurons, while substance P enhances this plasticity. An endocannabinoid CB1 receptor-mediated suppression of GABA_B receptor activity allows substance P to induce a long-lasting increase in glutamate release in LIPN neurons. Consistent with the substance P-dependent synaptic potentiation in the LIPN, the NK1R in the IPN is involved in fear extinction but not fear conditioning. Thus, our study describes a novel plasticity mechanism in the LIPN and a region-specific role of substance P in fear extinction.

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 pre-adolescent, adolescent and adult mice. Both pre-adolescent 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.

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 Ca2+-permeable AMPA receptor (CPAR)-dependent release of GABA from IPN neurons and a retrograde activation of GABAB 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.

The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene disrupts the activity-dependent release of BDNF, which might underlie its involvement in several neuropsychiatric disorders. Consistent with the potential role of regulated release of BDNF in synaptic functions, earlier studies have demonstrated that the BDNF Val66Met polymorphism impairs NMDA receptor-mediated synaptic transmission and plasticity in the hippocampus, the medial prefrontal cortex and the central amygdala. However, it is unknown whether the BDNF Val66Met polymorphism affects synapses in the dorsal striatum, which depends on cortical afferents for BDNF. Electrophysiological experiments revealed an enhanced glutamatergic transmission in the dorsolateral striatum (DLS) of knock-in mice containing the variant polymorphism (BDNFMet/Met) compared to the wild-type (BDNFVal/Val) mice. This increase in glutamatergic transmission is mediated by a potentiation in glutamate release and NMDA receptor transmission in the medium spiny neurons without any alterations in non-NMDA receptor-mediated transmission. We also observed an impairment of synaptic plasticity, both long-term potentiation and depression in the DLS neurons, in BDNFMet/Met mice. Thus, the BDNF Val66Met polymorphism exerts an increase in glutamatergic transmission but impairs synaptic plasticity in the dorsal striatum, which might play a role in its effect on neuropsychiatric symptoms. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

Of the two major subdivisions of the habenula, the medial and lateral nuclei, the medial habenula is the least understood in terms of synaptic transmission, intrinsic properties and plasticity. The medial habenula (MHb) is composed of glutamatergic neurons which receive the majority of their inputs from the septal region and project predominantly to the interpeduncular nucleus (IPN). To understand the synaptic transmission, we studied both glutamatergic and GABAergic synaptic transmission in the dorsal region of the medial habenula (dMHb). While glutamatergic transmission dominates during early development, an attenuation of glutamatergic transmission and an enhancement of GABAergic transmission occur during development leading into adulthood. Furthermore, as reported previously, GABAA receptor-mediated transmission is excitatory in the adult dMHb, which is consistent with the reduced expression of the K-Cl co-transporter KCC2. Given the potential role of the dMHb in aversive behaviors, we examined whether fear conditioning or exposure to foot shock affects excitability in dMHb neurons. We observed a suppression of the excitability of dMHb neurons in mice that either underwent fear conditioning or were exposed to foot shock. Furthermore, we observed a suppression of GABAergic but not glutamatergic transmission in the dMHb neurons following fear conditioning. These results suggest that aversive experience produces a suppression of the dMHb neuronal activity. Given that the medial habenula is upstream of the median raphe nucleus which is believed to be involved in the negative regulation of aversive memory, the suppression of dMHb neurons following an aversive experience might play a role in strengthening of aversive memories.

The oligomeric amyloid-beta (Abeta) peptide is thought to contribute to the subtle amnesic changes in Alzheimer's disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Abeta42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Abeta enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Abeta for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.

Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine] to potentiate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia. In addition, we show that CX546 administration also ameliorates various synaptic deficits induced by anesthesia, including reductions in synaptic expression of NMDA (N-methyl-d-aspartate) and AMPA receptor subunits, motor training-evoked neuronal activity, and dendritic spine remodeling associated with motor learning. Together, our results indicate that pharmacologically enhancing neuronal activity during the post-anesthesia recovery period could effectively reduce the adverse effects of early-life anesthesia.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite beta-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of beta-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of beta-hydroxybutyrate. Electrophysiological measurements indicate that beta-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.