Prefrontal Long-term Potentiation Research Articles

Age-Specific Modulation of Prefrontal Cortex LTP by Glucocorticoid Receptors Following Brief Exposure to HFD

The corticolimbic circuits in general and the medial prefrontal cortex in particular, undergo maturation during juvenility. It is thus expected that environmental challenges in forms of obesogenic diet can exert different effects in juvenile animals compared to adults. Further, the relationship between glucocorticoids and obesity has also been demonstrated in several studies. As a result, glucocorticoid receptor (GR) antagonists are currently being tested as potential anti-obesity agents. In the present study, we examined the effects of short-term exposure to high-fat diet (HFD) on prefrontal long-term potentiation (LTP) in both juvenile and adult rats, and the role of glucocorticoid receptors (GRs) in modulating these effects. We found HFD impaired prefrontal LTP in both juveniles and adults, but the effects of GR modulation were age- and diet-dependent. Specifically, GR antagonist RU-486 reversed the impairment of LTP in juvenile animals following HFD, and had no effect on control-diet animals. In adult animals, RU-486 has no effect on HFD-impaired LTP, but abolished LTP in control-diet animals. Furthermore, impairments in the prefrontal LTP following HFD are involved with an increase in the mPFC GR levels only in the juveniles. Further, we found that in vivo application of GR agonists into adult mPFC rescued HFD-induced impairment in LTP, suggesting that these receptors might represent strategic therapeutic targets to potentially combat obesity and metabolic related disorder.

Prefrontal Oxytocin is Involved in Impairments in Prefrontal Plasticity and Social Memory Following Acute Exposure to High Fat Diet in Juvenile Animals.

Juvenility represents a critical developmental phase during which exposure to a high fat diet (HFD) can severely modify cognitive and emotional functioning. The purpose of this study was to address how short and acute exposure to a HFD during juvenility affects social memory recognition and prefrontal long-term potentiation (LTP). As LTP and social memory depend on the neuromodulator oxytocin (OXY) and due to its role in metabolism, we also examined the effects of OXY in mediating HFD-induced alterations in social memory and LTP. Our results show that short exposure to a HFD during juvenility impairs social preference memory and prefrontal LTP. Interestingly, whereas systemic injections of OXY reversed the impairments in HFD-fed animals and impaired LTP and memory in control animals; prefrontal injections of the OXY agonist TGOT reversed the effects in HFD animals without affecting control animals. Exposure to HFD was associated with a reduction in the levels of OXY in the prefrontal compared to control animals. Interestingly, the restoration of social memory by TGOT in HFD animals was also associated with normalization of OXY in the prefrontal. These results point to a role that prefrontal OXY has in mediating the effects of HFD on memory and plasticity.

Deficits in LTP Induction by 5-HT2A Receptor Antagonist in a Mouse Model for Fragile X Syndrome

Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP) because of Fmr1 gene silencing. Serotonin (5-HT) is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR) is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca2+ concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.

Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: Implication of MEK signaling

We previously reported that exposure to acute and chronic stress impairs long-term potentiation (LTP) in the hippocampal–prefrontal cortex pathway and showed evidence for a fundamental role of the prefrontal cortex in maladaptive responses to stress. The goal of the current studies was to examine whether blockade of glucocorticosteroid receptors (GR), by mifepristone (a Type II glucocorticoid receptor antagonist), just after exposure to acute stress could prevent stress-induced impairment of prefrontal LTP. We further examine the effects of mifepristone on mitogen-activated protein/ERK kinase (MEK) signaling pathway in the prefrontal cortex. The data show that an acute injection of mifepristone after stress restored the stress-induced blockade of prefrontal LTP and reduction of phospho-Ser217/221-MEK. These findings have significance for the treatment of memory deficits in hypercortisolemic states, such as stress and depression.

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.

Phosphorylation of CREB and DARPP‐32 during late LTP at hippocampal to prefrontal cortex synapses in vivo

Specific patterns of stimulation applied in the ventral hippocampus produce long-term potentiation (LTP) of postsynaptic synapses in the prefrontal cortex in vivo. The induction of LTP is dependent on NMDA receptors and cAMP-dependant kinase (PKA) activation. Yet little is known concerning the cellular mechanisms underlying the expression of this neocortical form of LTP. In the present study, we tested whether LTP at hippocampal to prefrontal cortex synapses leads to activation of DARPP-32 and CREB as well as defined the temporal regulation of the phosphorylation states of both proteins. Our data indicate a peak in CREB and DARPP-32 phosphorylation during the late phase of prefrontal LTP (2 h posttetanus). These findings support the hypothesis that prolonged expression of hippocampal-prefrontal cortex LTP depends on a synergistic mechanism involving phosphorylation of both CREB and DARPP-32 via activation of the cAMP/PKA-dependent pathway.

Prefrontal infusion of PD098059 immediately after fear extinction training blocks extinction-associated prefrontal synaptic plasticity and decreases prefrontal ERK2 phosphorylation

A previous study has demonstrated that disruption of fear extinction-induced long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) is associated with the return of fear responding. Given that immediate posttraining infusion of PD098059, an inhibitor of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade, into the mPFC also promotes recovery of fear, we investigated whether impairment of mPFC ERK/MAPK cascade also interferes with development of extinction-related LTP in the mPFC in rats. In Experiment 1, extinction training consisting of repetitive presentations of a tone previously associated with eyelid-shock application induced LTP-like changes at hippocampal inputs to the mPFC that were evident for approximately 2 h following fear extinction. Infusion of PD098059 into the mPFC immediately after extinction training abolished training-related prefrontal LTP and impaired retention of extinction memory tested on the following day. In Experiment 2, immunoblotting assays revealed that posttraining infusion of PD098059 into the mPFC produced a significant reduction of mPFC ERK2. These data, along with previous findings, suggest that low levels of ERK2 phosphorylation in the mPFC may interfere with mechanisms of retention of extinction training. The involvement of mPFC LTP in fear extinction is discussed.

Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory

Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus. However, LTP in the prefrontal cortex is less well characterized than in the hippocampus. Here we report that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol. Furthermore, pharmacological or genetic blockade of the NR2B subunit in the cingulate cortex impaired the formation of early contextual fear memory. Our results demonstrate that the NR2B subunit of the NMDA receptor in the prefrontal cortex is critically involved in both LTP and contextual memory.