Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.     

NGF promotes long-term memory formation by activating poly(ADP-ribose)polymerase-1

Nerve growth factor (NGF) is a critical secreted protein that plays an important role in development, survival, and function of the mammalian nervous system. Previously reports suggest that endogenous NGF is essential for the hippocampal plasticity/memory and NGF deprivation induces the impairment of hippocampus-related memory and synaptic plasticity. However, whether exogenous supplement of NGF could promote the hippocampus-dependent synaptic plasticity/memory and the possible underlying mechanisms are not clear. In this study we found that NGF administration facilitates the hippocampus-dependent long-term memory and synaptic plasticity by increasing the activity of PARP-1, a polymerase mediating the PolyADP-ribosylation and important for the memory formation. Co-application of 3-Aminobenzamide (3-AB), a specific inhibitor of PARP-1, distinctly blocked the boosting effect of NGF on memory and synaptic plasticity, and the activation of downstream PKA-CREB signal pathway. Our data provide the first evidence that NGF supplement facilitates synaptic plasticity and the memory ability through PARP-1-mediated protein polyADP-ribosylation and activation of PKA-CREB pathway.     

Cocaine facilitates protein synthesis-dependent LTP: The role of metabotropic glutamate receptors

Cocaine addiction alters synaptic plasticity in many brain areas involved in learning and memory processes, including the hippocampus. Long-term potentiation (LTP) is one of the best studied examples of hippocampal synaptic plasticity and it is considered as one of the molecular basis of learning and memory. We previously demonstrated that in the presence of cocaine, a long lasting form of hippocampal LTP is induced by a single pulse of high frequency stimulation, which in normal conditions evokes only an early form of LTP. In this study, we further explore the molecular basis of this modulation of synaptic plasticity by cocaine. By performing pharmacological experiments on hippocampal slices, we were able to show that cocaine converts early LTP to a form of LTP dependent on protein synthesis, probably through the cAMP-dependent protein kinase and extracellular signal-regulated kinase signaling cascades. We also found that metabotropic glutamate receptors are involved in this phenomenon. These studies further clarify the molecular machinery used by cocaine to alter synaptic plasticity and modulate learning and memory processes.     

Dopaminergic modulation of hippocampus-dependent learning: blockade of hippocampal D1-class receptors during learning impairs 1-trial place memory at a 30-min retention delay

Consistent with the requirement of D1-class dopamine receptors for the induction of late (>3 h) hippocampal long-term potentiation (LTP), hippocampus-dependent 1-trial memory at long retention delays (>6 h) requires hippocampal D1-class receptors during learning. Hippocampal D1-class receptors also modulate the induction and magnitude of early LTP (<1-3 h). However, a corresponding modulation of the formation of hippocampus-dependent early (<1 h) memory remains to be revealed. We addressed this conceptually important issue, using a novel modification of the watermaze delayed-matching-to-place (DMP) test with an improved measure of hippocampus-dependent 1-trial place memory. On the DMP test, rats learn the novel location of a hidden escape platform on trial 1 of every day, so that 1-trial place memory can be measured on trial 2. Our new task modification includes the measurement of search preference for the correct location on trial 2 - a very sensitive index of hippocampus-dependent place memory. We examined the effects of hippocampal D1-class receptor blockade or stimulation during learning on memory at a 30-min retention delay. Bilateral hippocampal infusion of the D1-class receptor antagonist SCH23390 (1 or 5 μg/1 μl/side) before trial 1 dose-dependently impaired such early memory: rats infused with the higher dose showed reduced search preference for the correct location and took longer paths to reach this location. Infusion of the D1-class partial agonist SKF38393 (1 or 5 μg/1 μl/side) did not affect measures of 1-trial place memory. Our data reveal a behavioural correlate of the dopaminergic modulation of early LTP, thereby supporting the close correspondence between hippocampal LTP and hippocampus-dependent learning.     

Purinergic Signaling and Hippocampal Long-Term Potentiation

The purines ATP and adenosine are widely recognized for their neuromodulatory effects. They have been shown to have effects on neurons via various receptors and interactions with glial cells. In particular, long-term potentiation (LTP) in hippocampal slice preparations has been found to be modulated by ATP and adenosine. This review gives an overview of purinergic signaling in relation to hippocampal LTP and memory formation. The data supports the hypothesis that adenosine mediates a tonic suppression of synaptic transmission. Thus, low adenosine levels appear to increase basal synaptic activity via a decreased activation of the inhibitor A1 receptor, consequently making it more difficult to induce LTP because of lower contrast. During high stimulation, the inhibition of neighboring pathways by adenosine, in combination with an A2a receptor activation, appears to increase contrast of excited pathways against a nonexcited background. This would enable amplification of specific signaling while suppressing non-specific events. Although a clear role for purinergic signaling in LTP is evident, more studies are needed to scrutinize the modulatory role of ATP and adenosine and their receptors in synaptic plasticity and memory.     

Transient receptor potential vanilloid 1 agonists modulate hippocampal CA1 LTP via the GABAergic system

Transient receptor potential vanilloid 1 (TRPV1) was shown to modulate hippocampal CA1 pyramidal cell synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Synaptic plasticity is the cellular mechanism thought to mediate declarative learning and memory in the hippocampus. Although TRPV1 is involved in modulating hippocampal plasticity, it has yet to be determined how TRPV1 mediates its effects. Using field electrophysiology in hippocampal CA1 stratum radiatum we investigated how TRPV1 agonists modulate LTP, low frequency stimulation-induced LTD, and (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD. First we confirmed that TRPV1 agonists induce enhancement of CA1 pyramidal cell LTP in the absence the GABA_A receptor antagonist picrotoxin. Because it was recently determined that TRPV1 mediates a novel form of LTD in CA1 inhibitory GABAergic interneurons, which can disinhibit CA1 pyramidal cells, we used picrotoxin to block the effect of the GABAergic circuitry on CA1 LTP. When using picrotoxin, the TRPV1 agonist-induced enhancement of CA1 LTP was eliminated suggesting that the GABAergic circuitry is required for TRPV1 agonist mediated increases. Regarding LTD, in contrast to previously reported data, we did not see TRPV1 agonist-mediated effect on low frequency-induced stimulus LTD. However, during DHPG-induced LTD, TRPV1 was involved in the acute, but not the long-term depression phase of this plasticity. In summary, our findings support TRPV1 agonist involvement in hippocampal synaptic plasticity, including its enhancement of CA1 LTP. We demonstrate that the enhancement mediated by TRPV1 agonists requires GABA input to pyramidal cells thus providing a mechanism for how TRPV1 agonists modulate hippocampal synaptic plasticity.     

Prenatal melamine exposure induces impairments of spatial cognition and hippocampal synaptic plasticity in male adolescent rats

Our previous studies showed that chronic melamine exposure could affect hippocampal synaptic plasticity and impair learning and memory on adult rats. In this study, we investigated whether prenatal melamine exposure (PME) induced cognitive deficits and impairment of synaptic plasticity in postnatal offspring. An animal model was produced by melamine exposure throughout gestational period with 400 mg/kg/day, while male offspring rats were employed. Rats’ performance in Morris water maze (MWM) was tested to evaluate learning and memory. To examine the variations of paired-pulse facilitation (PPF) and synaptic plasticity, field excitatory postsynaptic potentials (fEPSPs) were recorded in hippocampal CA1 by stimulating Schaffer collaterals path. The result showed that PME probably impaired spatial learning and memory. The fEPSPs amplitudes of LTP were much lower and the PPF ratio was significantly higher in PME group than controls. These data suggested that PME impaired hippocampal synaptic function, which was partly involved in spatial cognition impairments.     

Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus

Neuronal development involves several discrete morphological steps requiring migration of newborn neurons to characteristic locations, extension of axons and dendrites into proper target regions, and formation of synapses with appropriate partners. Small GTPases such as Rac1, are believed to be critical regulators of these processes. We have previously reported that Rac1 is highly expressed in mouse hippocampus, where NMDA receptor activation causes Rac1 to translocate to the membrane in a manner similar to that observed in other non-neuronal cells. Additionally Rac1 has been seen to play a role in activation of signal transduction pathways associated with hippocampal learning and memory. Because of the established role of LTP and LTD in learning and memory processes, in this study we investigate whether Rac1 plays also an active and critical role in these types of long-term synaptic plasticity. We found that activation of Rac1 is associated with long-term plasticity, both LTP and LTD. Rac1 appears to have a transient role during the induction of NMDA receptor-dependent LTP, but does not have an effect on LTP maintenance and expression. Similar results were found for NMDA receptor-dependent induction of LTD, while mGluR-dependent LTD was shown to be significantly altered but not abolished. The results of these experiments provide essential knowledge regarding the signaling mechanisms that underlie synaptic plasticity, as well as learning and memory processes, which in turn offers insights into the basis of diseases involving memory impairment, such as Fragile X syndrome, Alzheimer's disease, William's syndrome, Angelman syndrome (AS), and schizophrenia.     

应激和环境对吗啡暴露大鼠的电生理和行为学影响的研究

目的:研究平台应激、急性吗啡暴露对4周龄和10周龄♂W istar大鼠海马CA1区突触可塑性及空间记忆的影响以及研究丰富环境对大鼠学习记忆、吗啡诱导的条件性位置偏爱(cond itioned p lace preference,CPP)及海马CA1区突触可塑性的影响。方法:电生理实验(在体和离体)和行为学方法(水迷宫和CPP实验),统计采用方差分析(ANOVA)和t检验。结果与结论:(1)慢性应激和/或急性吗啡暴露分别对4周龄和10周龄这两个年龄段的LTP和LTD具有不同作用,存在明显的年龄差异。(2)急性平台应激损害4周龄和10周龄大鼠的记忆,但年龄差异没有显著性;慢性平台应激对10周龄大鼠记忆起易化作用,对4周龄没有明显的影响。(3)急性吗啡暴露(2 mg.kg-1)对4周龄大鼠的记忆有损害作用,而对10周龄大鼠的记忆没有影响。(4)急性应激加吗啡损害了4周龄大鼠的记忆保持,而对10周龄大鼠的记忆保持无影响;慢性应激加吗啡对4周龄大鼠的记忆保持无影响,对10周龄大鼠的记忆保持有易化作用。(5)丰富环境可以增强大鼠的空间学习和记忆能力,增强了吗啡诱导的CPP可能与学习和记忆能力的提高有关;同时,丰富环境对吗啡依赖所致的突触可塑性的损害有保护作用。丰富环境能逆转早期应激所产生的对学习记忆和突触可塑性的损害。     

皮质酮对大鼠海马颗粒细胞层长时程增强效应的抑制作用(英文)

通过胞外记录大鼠海马颗粒细胞层诱发电位观察了皮质酮对麻醉大鼠海马神经突触可塑性的影响． 结果显示,皮质酮（１, ４ 和１０ ｍ ｇ·ｋｇ－ １, ｉｐ）有使单刺激大鼠海马颗粒细胞层基础群峰电位（ＰＳ）幅度升高的趋势,但同对照相比无显著性差异． 给予大鼠穿行通路以串刺激（６０ Ｈｚ, ３０ 次）可使海马颗粒细胞层ＰＳ幅度持续增高,增幅达７０％ － ８０％ ,说明在海马诱生长时程增强效应（ＬＴＰ）． 预先１ ｈ给予大鼠皮质酮（１, ４ 和１０ ｍ ｇ·ｋｇ－ １, ｉｐ）可剂量依赖地降低串刺激诱导的ＰＳ幅度的升高,说明皮质酮可抑制海马颗粒细胞层ＬＴＰ的诱生． 结果提示,皮质酮可损伤大鼠海马神经突触可塑性．     

Inhibition of tetanically sciatic stimulation-induced LTP of spinal neurons and Fos expression by disrupting glutamate transporter GLT-1

Tetanic stimulation of the sciatic nerve produces spinal long-term potentiation (LTP) of C-fiber evoked field potentials, which is NMDA dependent and may be the substrate of inflammation- or nerve injury-produced central sensitization. Glial glutamate transporter GLT-1 has been considered as an important regulator of excitatory synaptic transmission and nociception. In the present study, we investigated the effects of GLT-1 on the spinal LTP and Fos expression induced by tetanically sciatic stimulation. Intrathecal administration of dihydrokainate (DHK), a GLT-1 selective inhibitor, partially inhibited (0.1 mM) or completely blocked (3.0 mM) the spinal LTP, which may be related to an accumulation of extracellular glutamate. Intrathecal DHK (3.0 mM) also suppressed tetanic stimulation-induced spinal Fos expression. Double immunofluorescence showed no Fos expression in glial fibrillary acidic protein (GFAP)-positive cells, and the cell DNA fragment study failed to detect a significant apoptosis of spinal neurons. These results suggest that disruption of GLT-1 may be associated with the inhibition of functional activation of spinal neurons expressing Fos, but not with glutamate excitotoxicity. In conclusion, glial GLT-1 may play an important role in tetanically sciatic stimulation-induced LTP of spinal nociceptive neurons via the regulation of extracellular levels of glutamate to an appropriate concentration.     

Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus

Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead.     

The induction of long-term potentiation at amygdalo-hippocampal synapses in vivo

Electrical stimulation of the basolateral amygdala (BLA) evoked synaptic potentials in the dentate gyrus (DG) of the hippocampus in anesthetized rats. To determine if this pathway possesses synaptic plasticity, we investigated the impact of several conditions of high-frequency stimulation on BLA-DG synaptic potentials in these rats. Application of two trains of 100-pulse, 100-Hz stimulation or theta-burst stimulation to the BLA reproducibly induced long-term potentiation (LTP) of BLA-DG synaptic potentials. Paired-pulse facilitation was unchanged during LTP, suggesting that postsynaptic mechanisms are involved in the expression of LTP. In addition, the induction of LTP was not affected by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate, suggesting that activation of NMDA receptors is not required. This novel form of LTP should be a valuable model for elucidating neural mechanisms underlying the formation of emotional memory.     

皮质酮对大鼠海马颗粒细胞层长时程增强效应的抑制作用

通过胞外记录大鼠海马颗粒细胞层诱发电位观察了皮质酮对麻醉大鼠海马神经突触可塑性的影响. 结果显示,皮质酮(1, 4 和10 mg·kg^-1, ip)有使单刺激大鼠海马颗粒细胞层基础群峰电位(PS)幅度升高的趋势,但同对照相比无显著性差异. 给予大鼠穿行通路以串刺激(60 Hz, 30次)可使海马颗粒细胞层PS幅度持续增高,增幅达70%-80%,说明在海马诱生长时程增强效应(LTP). 预先1 h给予大鼠皮质酮(1, 4和10 mg·kg^-1, ip）可剂量依赖地降低串刺激诱导的PS幅度的升高,说明皮质酮可抑制海马颗粒细胞层LTP的诱生. 结果提示,皮质酮可损伤大鼠海马神经突触可塑性.     

The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats

It has not been uniform to date that the Ginkgo biloba extracts enhance cognitive function in aged animals, and the mechanisms of action remain difficult to elucidate. In this study, the Morris water maze task and electrophysiological methods were used to study the effects of repeated daily administration of EGb 761, a standardized extract from G. biloba leaves, on hippocampal-dependent spatial learning and memory and synaptic plasticity of aged rats. The adult subjects perform the Morris water maze task better than aged rats, as a cellular mechanism, the hippocampal long-term potentiation (LTP) elicited from adult animals is robust (139.29+/-2.7%). In addition, the spatial learning and memory of aged rats that had been fed on an EGb 761-supplemented diet (60 mg kg(-1)) for 30 days were significantly better than those of control aged rats. The magnitude of LTP (116.63+/-3.6%) recorded in vivo from the hippocampus CA1 area of aged rats was significantly enhanced by EGb 761 (60 mg kg(-1)). In conclusion, the spatial learning and memory of aged rats is worse than that of young subjects, and EGb 761, acting as a 'cognitive enhancer', has benefit on synaptic plasticity and cognition in aged rats. The present data further confirmed that enhancement of synaptic plasticity of the hippocampus might ameliorate the deficit in spatial learning and memory in aged rats.     

Tetrahydroxystilbene glucoside, a plant-derived cognitive enhancer, promotes hippocampal synaptic plasticity

Plant or food derived polyphenols have received a great deal of attention due to their biological properties including anti-oxidative effects, neuroprotection and memory enhancement. Here, we investigated the roles of 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), an active component of the rhizome extracted from Polygonum multiflorum, in the regulation of hippocampal synaptic plasticity in normal mice as well as the underlying mechanisms. It was shown that TSG promoted the differentiation of PC12 cells and increased the intracellular calcium level in hippocampal neurons. TSG facilitated high-frequency stimulation (HFS)-induced hippocampal long-term potentiation (LTP) in a bell-shaped manner. The facilitation of LTP induction by TSG required calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) activation. Taken together, our data demonstrate that TSG promotes LTP induction and this effect may contribute to the enhancement of learning and memory seen in animal models.     

MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity.     

Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome

Due to the homology between human chromosome 21 and mouse chromosome 16, trisomy 16 mice are considered animal models of Down syndrome (DS). Abnormal hippocampal synaptic plasticity and behavior have been reported in the segmental trisomy 16 Ts65Dn mouse. In the Ts1Cje DS mouse model, which has a shorter triplicated chromosomal segment than Ts65Dn, more subtle hippocampal behavioral deficits have been reported. In this study, we investigated CA1 hippocampal synaptic plasticity, long-term potentiation (LTP) and depression (LTD) in the Ts1Cje mouse. Field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 area of in vitro hippocampal slices from the Ts1Cje mouse and diploid controls, LTP was induced by a single tetanizing train pulse (1 s) at 100 Hz and LTD by a 900-pulse train at 1 Hz. We report for the first time that compared to diploid controls, the hippocampus from the Ts1Cje mouse had a smaller LTP and an increased LTD. The changes are less dramatic than had been reported previously for the Ts65Dn mouse. Furthermore, in the Ts1Cje mouse trains of pulses at both 20 Hz and 100 Hz produced a decrease in the evoked fEPSPs over the length of the train in comparison to diploid fEPSPs. These findings suggest that genes from Ts1Cje chromosome, including GIRK2 potassium channel, contribute to abnormal short- and long-term plasticity.     

MAPK级联信号通路与长时程增强

长时程增强(long-term potentiation,LTP)被认为是与学习记忆密切相关的神经突触可塑性的生物学基础,多种信号通路参与了LTP的诱导与维持。丝裂原活化蛋白激酶(m i-togen-activated prote in k inases,MAPK)级联信号通路是介导细胞反应的重要信号系统,是细胞外信号从细胞表面传导到细胞核内部的重要传递途径,在细胞的增殖、分化和调亡过程中发挥重要作用。研究表明,MAPK的上游调节物质和下游作用分子在神经元中广泛存在,MAPK级联信号通路通过磷酸化神经元参与LTP诱导与维持的多种受体和酶,进而发挥对LTP的调节作用,影响神经突触可塑性。该文综述了细胞外信号调节激酶(extracellu lar signal-regu lated k inase,ERK)、c-Jun氨基端激酶(c-JunN-term inal k inase,JNK)和p38 3条MAPK通路对LTP的调节作用。     

Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression

An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments.