Enhancement Of Long-term Potentiation Research Articles

Prenatal ethanol exposure enhances NMDAR‐dependent long‐term potentiation in the adolescent female dentate gyrus

The dentate gyrus (DG) is a region of the hippocampus intimately involved with learning and memory. Prenatal exposure to either stress or ethanol can reduce long-term potentiation (LTP) in the male hippocampus but there is little information on how these prenatal events affect LTP in the adolescent female hippocampus. Previous studies suggest that deleterious effects of PNEE can, in part, be mediated by corticosterone, suggesting that prenatal stress might further enhance any alterations to LTP induced PNEE. When animals were exposed to a combination of prenatal stress and PNEE distinct sex differences emerged. Exposure to ethanol throughout gestation significantly reduced DG LTP in adolescent males but enhanced LTP in adolescent females. Combined exposure to stress and ethanol in utero reduced the ethanol-induced enhancement of LTP in females. On the other hand, exposure to stress and ethanol in utero did not alter the ethanol-induced reduction of LTP in males. These results indicate that prenatal ethanol and prenatal stress produce sex-specific alterations in synaptic plasticity in the adolescent hippocampus.

Activation of nicotinic α7 acetylcholine receptor enhances long term potentation in wild type mice but not in APPswe/PS1ΔE9 mice

Amyloid β (Aβ) plays a central role in Alzheimer's disease (AD) and binds to the nicotinic α7 receptor (α7 nAChR). Little is known about the degree to which the binding of Aβ to the α7 nAChR influences the role of this receptor in long-term potentiation (LTP), however. We have studied the effect of the partial α7 nAChR agonist SSR180711 on hippocampal slice preparations from normal wild type (Wt) and APPswe/PS1ΔE9 transgenic (Tg) mice. In the hippocampal slices from the 6 months old Wt mice, the application of both nicotine (5μM) and SSR180711 (300nM) resulted in a significant enhancement of LTP expressed in area CA1. However, in the Tg mice the application of SSR180711 did not result in an increase in LTP beyond control levels. The amount of binding of the α7 nAChR ligand 125-I-α-bungarotoxin was not different between in Tg and Wt mice. These findings indicate that the α7 nAChR is functionally blocked in the hippocampal neurons, downstream of the α7 nAChR, and that this is likely due to an interaction between the receptor and Aβ, which leads to changes in LTP.

Roles of two subtypes of corticotrophin‐releasing factor receptor in the corticostriatal long‐term potentiation under cocaine withdrawal condition

The roles of two subtypes of corticotrophin-releasing factor (CRF) receptor in corticostriatal synaptic plasticity under cocaine withdrawal condition were examined in this study. Neither the resting membrane potential and input resistance of striatal neurons nor the long-term potentiation (LTP) of corticostriatal slices were affected by cocaine withdrawal. CRF dose-dependently enhanced in vitro corticostriatal LTP in rats from both cocaine-withdrawal and saline-control groups. Yet, the enhancement of corticostriatal LTP by CRF (20, 40, 80 nM) was significantly greater in the cocaine-withdrawal group than in the control group. CRF(1)-selective antagonist (NBI 27914, 100 nM) attenuated the CRF-induced enhancement of corticostriatal LTP in both groups, whereas the CRF(2)-selective antagonist (astression2B, 100 nM) attenuated the enhanced corticostriatal LTP only in the cocaine-withdrawal group. Importantly, urocortin2 (a CRF(2)-selective agonist, 40 nM) selectively increased corticostriatal LTP in the cocaine-withdrawal group, but not in the saline controls. The urocortin2-induced enhancement of LTP was totally blocked by astression2B (100 nM). These results suggest that the CRF system modulate neuroadaptive changes in the corticostriatal circuit during cocaine withdrawal, and the CRF(2) in this area mediate an important mechanism that contributes to the relapse of cocaine addiction.

Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice

Calcium/calmodulin-dependent kinase IV (CaMKIV) phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB), which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP) in the anterior cingulate cortex (ACC) was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training) in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.

Pathologically Activated Neuroprotection via Uncompetitive Blockade of N-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.

Effect of agmatine on long-term potentiation in morphine-treated rats

Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5–10 mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30 mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10 mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5 mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor.

Cocaine enhancement of long‐term potentiation in the CA1 region of rat hippocampus: Lamina‐specific mechanisms of action

There is an expanding body of work characterizing dopaminergic modulation of synaptic plasticity in the hippocampus CA1 region, an area known to be involved in learning and memory. However, in vitro studies to date have focused almost exclusively on the proximal and distal apical dendritic layers (strata radiatum and lacunosum moleculare, respectively). In this report, we establish that dopaminergic activity can enhance long-term potentiation (LTP) in the basal dendritic layer (stratum oriens) of CA1 in the rat hippocampal slice preparation. Application of the D(1/5) agonist SKF38393 (20 microM) significantly increased the magnitude of basal LTP of the fEPSP response following high-frequency stimulation of the Schaffer collateral/commissural inputs in the stratum oriens layer. In addition, endogenous dopamine (DA) activity facilitated by the presence of cocaine (6 muM) was also capable of enhancing the magnitude of basal LTP. Prior application of the D(1/5) antagonist SKF83566 (2 muM) prevented this effect of cocaine, indicating that endogenously released dopamine was exerting its LTP-enhancing effect in stratum oriens via activation of D(1/5) receptors. This final result stands in contrast with the previously characterized effects of cocaine on apical LTP in the stratum radiatum, which instead have been shown to require D(3) receptor activation. These observations demonstrate that dopaminergic mechanisms resulting in the enhancement of hippocampal LTP are lamina specific at Schaffer collateral/commissural synapses in the CA1 region. Synapse 2010. (c) 2010 Wiley-Liss, Inc.

Time-dependent changes in learning ability and induction of long-term potentiation in the lithium–pilocarpine-induced epileptic mouse model

To explore the mechanism underlying the development of learning deficits in patients with epilepsy, we generated a mouse model for temporal lobe epilepsy by intraperitoneally injecting mice with pilocarpine with lithium chloride, and investigated time-dependent changes in both contextual fear memory of those model mice and long-term potentiation (LTP) in hippocampal CA1 neurons 1day, 2weeks, and 6weeks after the onset of status epilepticus (SE). Fear memory formation did not change 1day and 2weeks after the onset of SE, but was significantly reduced after 6weeks. Induction of LTP was enhanced 1day after the onset of SE, but returned to the normal level 2weeks later, and was almost completely attenuated after 6weeks. The enhancement of LTP was accompanied by an increase in output responses of excitatory postsynaptic potentials, whereas suppression of LTP was accompanied by alteration of the ratio of paired pulse facilitation. These results indicate that time-dependent changes of LTP induction have a causal role in the development of learning deficits of epilepsy patients.

Dopamine receptor mechanisms mediate corticotropin‐releasing factor‐induced long‐term potentiation in the rat amygdala following cocaine withdrawal

Corticotropin-releasing factor (CRF) in the amygdala is involved in stress responses. Moreover, dopaminergic neurotransmission in the brain reward system including the amygdala plays a significant role in the pathology of cocaine addiction. The present study analysed CRF-induced synaptic plasticity, its pharmacological sensitivity and interactions with the dopamine (DA) system in the basolateral to lateral capsula central amygdala (lcCeA) pathway after a 2-week withdrawal from repeated cocaine administration. A physiologically relevant CRF concentration (25 nm) induced long-term potentiation (LTP) that was enhanced after cocaine withdrawal. In saline-treated rats, CRF-induced LTP was mediated through N-methyl-d-aspartate (NMDA) receptors, L-type voltage-gated calcium channels (L-VGCCs) and CRF(1) receptors. However, in cocaine-withdrawn animals, activation of CRF(1) and CRF(2) receptors was found to enhance LTP. This enhanced CRF-induced LTP after cocaine withdrawal was mediated through endogenous activation of both D1- and D2-like receptors. Furthermore, expression of the D1 receptor (D1R) but not the D2R, D3R, D4R or D5R was significantly increased after cocaine withdrawal. CRF(1) but not CRF(2) protein expression was increased, suggesting that elevated levels of these proteins contributed to the enhancement of CRF-induced LTP during cocaine withdrawal. CRF interactions with the DA system in the amygdala may represent a fundamental neurochemical and cellular mechanism linking stress to cocaine-induced neuronal plasticity.

Repeated restraint-induced modulation of long-term potentiation in the dentate gyrus of the mouse

We studied the potential for induction of long-term potentiation (LTP) in slices of the dentate gyrus of C57BL/6 mouse, prepared 24 h after 1, 3, 7, 14 or 21 successive daily neck restraint sessions lasting for 10 min. In slices from control animals and mice restrained only once, LTP (155 ± 2% of baseline) was evident for at least 2 h, but LTP was impaired after 3 sessions of neck restraint. This effect could be blocked by administration of the glucocorticoid receptor (GR) antagonist RU38486 before each restraint. One day after 3 restraint sessions the levels of plasma corticosterone, GR and mineralocorticoid receptor (MR) proteins remained elevated. After 7 neck restraint sessions the LTP level returned to normal; after 14 and 21 restraint sessions LTP was enhanced. LTP enhancement after 14 daily restraint sessions was not blocked by the GR antagonist RU38486 administered before each restraint; the MR antagonist RU28318 blocked LTP induction completely. After 14 daily restraint sessions the level of GR and MR proteins did not differ from the control and the plasma corticosterone level remained slightly elevated. These data indicate that repeated stress imposed by brief neck restraint bidirectionally modulates the potential for LTP in the dentate gyrus in a manner dependent on the number of daily restraint sessions.

Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice

Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and they are widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of statins extend to the CNS. Statins have been shown to improve the outcome of stroke and traumatic brain injury, and statin use has been associated with a reduced prevalence of Alzheimer's disease (AD) and dementia. However, prospective studies with statins in AD have produced mixed results. Recently, we reported that simvastatin, a widely used statin in humans, enhances learning and memory in non-transgenic mice as well as in transgenic mice with AD-like pathology on a mixed genetic background. However, the cellular and molecular mechanisms underlying the beneficial effects of simvastatin on learning and memory remain elusive. The present study was undertaken to investigate the effect of acute simvastatin treatment on hippocampal long-term potentiation (LTP), a cellular model of learning and memory, in brain slices from C57BL/6 mice. Our results demonstrate that a prolonged in vitro simvastatin treatment for 2–4 h, but not a short-term 20-min exposure, significantly increases the magnitude of LTP at CA3–CA1 synapses without altering basal synaptic transmission or the paired-pulse facilitation ratio in hippocampal slices. Furthermore, we show that phosphorylation of Akt (protein kinase B) is increased significantly in the CA1 region following 2-hour treatment with simvastatin, and that inhibition of Akt phosphorylation suppresses the simvastatin-induced enhancement of LTP. These findings suggest activation of Akt as a molecular pathway for augmented hippocampal LTP by simvastatin treatment, and implicate enhancement of hippocampal LTP as a potential cellular mechanism underlying the beneficial effects of simvastatin on cognitive function.

Are CB1 receptor antagonists nootropic or cognitive impairing agents?

For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB(1) receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB(1) receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB(1) receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB(1) receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB(1) receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB(1) receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB(1) receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories.

Synaptic Adaptations of CA1 Pyramidal Neurons Induced by a Highly Effective Combinational Antidepressant Therapy

Antidepressants (AD) need to be chronically administered (weeks to months) to provide beneficial effects. Evidence suggests that combined administration of inhibitors of monoamine reuptake and phosphodiesterase type 4 allows a highly effective therapeutic action. Also, this coadministration more rapidly boosts the cyclic adenosine monophosphate (cAMP) pathway, which is normally activated during chronic treatment of single compounds. Little is known, however, about how this augmentation therapy affects the core mechanism of glutamatergic plasticity. We therefore investigated how in vivo combinational subchronic rolipram and imipramine (scRI) treatment affects depressive behavior, cAMP-dependent transcription, and glutamatergic transmission in the hippocampus, a region critically implicated in depression. Antidepressant properties of scRI were investigated through the forced swim test. Changes in cAMP-dependent transcription and synaptic transmission of CA1 pyramidal cells were explored with green fluorescent protein, enzyme-linked immunosorbent assay, electrophysiology recordings, and Golgi-Cox staining. We demonstrate that scRI displays robust antidepressant properties compared with single-drug treatments and increases hippocampal c-Fos expression and brain-derived neurotrophic factor protein levels. These effects are accompanied by a specific increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in already existing synapses. Finally, both acute and subchronic treatments led to enhancement of long-term potentiation but differently affected spine density and morphology, with scRI administration specifically resulting in a large increase in stubby spines. We conclude that scRI is highly effective in providing antidepressive effects, including the hippocampal transcriptional alterations normally observed with longer single-drug treatments. Furthermore, we identified scRI-induced modifications in glutamatergic transmission that probably underlie the beneficial action of this combinational therapy.

Transient prenatal vitamin D deficiency is associated with changes of synaptic plasticity in the dentate gyrus in adult rats

Transient prenatal vitamin D deficiency is considered a neurodevelopmental animal model in schizophrenia research. Vitamin D deficiency in female rats causes morphological, cellular and molecular changes in the brain and alters behaviour and nerve growth factors expression in their offspring. Prenatal depleted animals showed a significant impairment of latent inhibition, a feature often associated with schizophrenia and of hole board habituation. Interestingly, memory consolidation of brightness discrimination was improved. Possible functional effects of altered brain development that results from prenatal vitamin D deficiency were characterized by investigation of potentiation phenomena in the hippocampus in freely moving rats. Transient prenatal vitamin D deficiency induced an enhancement of long-term potentiation (LTP) using either weak tetanic or strong tetanic stimulation, whereas the response to test stimuli was not changed. The classic neuroleptic drug haloperidol (Hal) and the atypical neuroleptic risperidone (Ris) in doses, which normalized behavioural disturbances in prenatal vitamin D-deficient animals without any side effects on the normal behaviour decreased the enhanced LTP in the experimental group to control level. Interestingly, the effect of the substances was different in experimental and control rats. The LTP was enhanced in control animals by the low doses of the drugs effective in our behavioural experiments. It can be suggested, that changes in brain development induced by prenatal vitamin D deficiency lead to specific functional alterations in hippocampal synaptic plasticity. LTP is considered a cellular correlate of learning and memory. The better retention performance in brightness discrimination seems in accordance with enhanced potentiation level.

NR2B subunit‐dependent long‐term potentiation enhancement in the rat cortical auditory system in vivo following masking of patterned auditory input by white noise exposure during early postnatal life

The composition of N-methyl-D-aspartate (NMDA) receptor subunits influences the degree of synaptic plasticity expressed during development and into adulthood. Here, we show that theta-burst stimulation of the medial geniculate nucleus reliably induced NMDA receptor-dependent long-term potentiation (LTP) of field postsynaptic potentials recorded in the primary auditory cortex (A1) of urethane-anesthetized rats. Furthermore, substantially greater levels of LTP were elicited in juvenile animals (30-37 days old; approximately 55% maximal potentiation) than in adult animals (approximately 30% potentiation). Masking patterned sound via continuous white noise exposure during early postnatal life (from postnatal day 5 to postnatal day 50-60) resulted in enhanced, juvenile-like levels of LTP (approximately 70% maximal potentiation) relative to age-matched controls reared in unaltered acoustic environments (approximately 30%). Rats reared in white noise and then placed in unaltered acoustic environments for 40-50 days showed levels of LTP comparable to those of adult controls, indicating that white noise rearing results in a form of developmental arrest that can be overcome by subsequent patterned sound exposure. We explored the mechanisms mediating white noise-induced plasticity enhancements by local NR2B subunit antagonist application in A1. NR2B subunit antagonists (Ro 25-6981 or ifenprodil) completely reversed white noise-induced LTP enhancement at concentrations that did not affect LTP in adult or age-matched controls. We conclude that white noise exposure during early postnatal life results in the maintenance of juvenile-like, higher levels of plasticity in A1, an effect that appears to be critically dependent on NR2B subunit activation.

Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice

Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCalpha (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIalpha (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCalpha (Ser657) and CaMKIIalpha (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (+/-)-alpha-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIalpha (Thr286) and PKCalpha (Ser657), respectively.

Galantamine enhancement of long‐term potentiation is mediated by calcium/calmodulin‐dependent protein kinase II and protein kinase C activation

Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA-induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long-term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01-10 microM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase Calpha (PKCalpha) activities with a bell-shaped dose-response curve peaked at 1 microM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine-rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCalpha. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell-shaped CaMKII and PKCalpha activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell-shaped dose-response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 microM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with alpha7-type nAChR activation. These results suggest that galantamine potentiates NMDA receptor-dependent LTP through alpha7-type nAChR activation, by which the postsynaptic CaMKII and PKC are activated.

Signaling through cGMP-Dependent Protein Kinase I in the Amygdala Is Critical for Auditory-Cued Fear Memory and Long-Term Potentiation

Long-term potentiation (LTP) of inputs relaying sensory information from cortical and thalamic neurons to principal neurons in the lateral amygdala (LA) is thought to serve as a cellular mechanism for associative fear learning. Nitric oxide (NO), a messenger molecule widely implicated in synaptic plasticity and behavior, has been shown to enhance LTP in the LA as well as consolidation of associative fear memory. Additional evidence suggests that NO-induced enhancement of LTP and amygdala-dependent learning requires signaling through soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (cGK). Mammals possess two genes for cGK: the prkg1 gene gives rise to the cGK type I isoforms, cGKIalpha and cGKIbeta, and the prkg2 gene encodes the cGK type II. Reportedly, both cGKI and cGKII are expressed in the amygdala, and cGKII is involved in controlling anxiety-like behavior. Because selective pharmacological tools for individual cGK isoforms are lacking, we used different knock-out mouse models to examine the function of cGKI and cGKII for LTP in the LA and pavlovian fear conditioning. We found robust expression of the cGKI specifically in the LA with cGKIbeta as the prevailing isoform. We further show a marked reduction of LTP at both thalamic and cortical inputs to the LA and a selective impairment of auditory-cued fear memory in cGKI-deficient mutants. In contrast, cGKII null mutants lack these phenotypes. Our data suggest a function of cGKI, likely the beta isoform, in the LA, supporting synaptic plasticity and consolidation of fear memory.

Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.

Removal of FKBP12 Enhances mTOR-Raptor Interactions, LTP, Memory, and Perseverative/Repetitive Behavior

FK506-binding protein 12 (FKBP12) binds the immunosuppressant drugs FK506 and rapamycin and regulates several signaling pathways, including mammalian target of rapamycin (mTOR) signaling. We determined whether the brain-specific disruption of the FKBP12 gene in mice altered mTOR signaling, synaptic plasticity, and memory. Biochemically, the FKBP12-deficient mice displayed increases in basal mTOR phosphorylation, mTOR-Raptor interactions, and p70 S6 kinase (S6K) phosphorylation. Electrophysiological experiments revealed that FKBP12 deficiency was associated with an enhancement in long-lasting hippocampal long-term potentiation (LTP). The LTP enhancement was resistant to rapamycin, but not anisomycin, suggesting that altered translation control is involved in the enhanced synaptic plasticity. Behaviorally, FKBP12 conditional knockout (cKO) mice displayed enhanced contextual fear memory and autistic/obsessive-compulsive-like perseveration in several assays including the water maze, Y-maze reversal task, and the novel object recognition test. Our results indicate that FKBP12 plays a critical role in the regulation of mTOR-Raptor interactions, LTP, memory, and perseverative behaviors.