Decreased thalamo-cortical connectivity by alteration of neural information flow in theta oscillation in depression-model rats

Alterations in oscillatory brain activity are strongly correlated with cognitive performance in various physiological rhythms. The present study investigated whether the directionality of neural information flow (NIF) could be used to characterize the synaptic plasticity in thalamocortical (TC) pathway, and examined which frequency field oscillations were mostly related to the cognitive deficiency in depression. Two novel algorithms were employed to determine the coupling interaction between the LD thalamus and medial prefrontal cortex (mPFC) in five frequency bands, using the phase signals of local field potentials (LFP) in these two regions. The results showed that the power of neural activity in mPFC was increased in delta, theta and beta frequency bands in depression. However, the nonlinear characteristics of LFP activity were weakened in depression by means of sample entropy measurements. In the analysis of phase dynamics, the phase synchronization values were reduced in theta rhythm in stressed rats. Importantly, the coupling direction index d and the unidirectional influence from LD thalamus to mPFC were significantly reduced at the theta rhythm in rats in depression, and increased after memantine treatment, which were associated with the LTP alterations and cognitive impairment in our previous report. Moreover, the fact that the reduced entropy value was only found in mPFC might implicate postsynaptic effect involved in synaptic plasticity alteration in the depression model. The results suggest that the effects of depression on cognitive deficits are mediated via profound alterations in information flow in the TC pathway, and the directional index at theta rhythm could be used as a measurement of synaptic plasticity.     

MGluR5 mediates the interaction between late-LTP, network activity, and learning

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5-10 Hz) and gamma (30-100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.     

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.     

A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells.     

Astrocytes mediate in vivo cholinergic-induced synaptic plasticity

Long-term potentiation (LTP) of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca²⁺ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR) and metabotropic glutamate receptor (mGluR) activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca²⁺ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP) also involves mGluR activation. Astrocyte Ca²⁺ elevations and LTP are absent in IP₃R2 knock-out mice. Downregulating astrocyte Ca²⁺ signal by loading astrocytes with BAPTA or GDPβS also prevents LTP, which is restored by simultaneous astrocyte Ca²⁺ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca²⁺ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergic-induced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca²⁺ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca²⁺ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information.     

Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats

Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca²⁺-permeable AMPA receptors (CP-AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP) after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning.     

学习过程中MF－CA3与PP－CA3突触传递效应的变化

应用慢性电极埋植技术以电生理学结合行为学的方法,探查在学习过程中大鼠海马ＣＡ３区两种不同输入突触（ＭＦ－ＣＡ３突触和ＰＰ－ＣＡ３突触）的可塑性变化及其相互关系。结果如下：（１）在分辨反应的建立过程中,在ＣＡ３区由ＭＦ诱发（ＭＦ－ＣＡ３）的群体锋电位（ｐｏｐｕｌａｔｉｏｎｓｐｉｋｅ,ＰＳ）和由ＰＰ诱发（ＰＰ－ＣＡ３）的群体锋电位,两者的峰值同步增大,同步达最高水平,且ＰＳ峰值达最高水平先于行为反应达学会标准;（２）在自然消退过程中,两者的ＰＳ峰值也是同步恢复至训练前水平的。结果表明,在ＣＡ３区这两种输入突触的习得性ＬＴＰ的产生和消退都是同步的,提示了它们之间可能具有协同作用。     

Impaired long-term memory and long-term potentiation in N-type Ca2+ channel-deficient mice

Voltage-dependent N-type Ca(2+) channels, along with the P/Q-type, have a crucial role in controlling the release of neurotransmitters or neuromodulators at presynaptic terminals. However, their role in hippocampus-dependent learning and memory has never been examined. Here, we investigated hippocampus-dependent learning and memory and synaptic plasticity at hippocampal CA3-CA1 synapses in mice deficient for the alpha(1B) subunit of N-type Ca(2+) channels. The mutant mice exhibited impaired learning and memory in the Morris water maze and the social transmission of food preference tasks. In particular, long-term memory was impaired in the mutant mice. Interestingly, among activity-dependent long-lasting synaptic changes, theta burst- or 200-Hz-stimulation-induced long-term potentiation (LTP) was decreased in the mutant, compared with the wild-type mice. This type of LTP is known to require brain-derived neurotrophic factor (BDNF). It was found that both BDNF-induced potentiation of field excitatory postsynaptic potentials and facilitation of the frequency of miniature excitatory postsynaptic currents (mEPSCs) were reduced in the mutant. Taken together, these results demonstrate that N-type Ca(2+) channels are required for hippocampus-dependent learning and memory, and certain forms of LTP.     

Eugenol depresses synaptic transmission but does not prevent the induction of long-term potentiation in the CA1 region of rat hippocampal slices

Using field potential recording in the CA1 region of the rat hippocampal slices, the effects of eugenol on synaptic transmission and long-term potentiation (LTP) were investigated. Population spikes (PS) were recorded in the stratum pyramidal following stimulation of stratum fibers. To induce LTP, eight episodes of theta pattern primed-bursts (PBs) were delivered. Eugenol decreased the amplitude of PS in a concentration-dependent manner. The effect was fast and completely reversible. Eugenol had no effect on PBs-induced LTP of PS. It is concluded that while eugenol depresses synaptic transmission it does not affect the ability of CA1 synapses for tetanus-induced LTP and plasticity.     

Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.     

Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses

Brain-derived neurotrophic factor (BDNF) has been implicated in several forms of long-term potentiation (LTP) at different hippocampal synapses. Using two-photon imaging of FM 1-43, a fluorescent marker of synaptic vesicle cycling, we find that BDNF is selectively required for those forms of LTP at Schaffer collateral synapses that recruit a presynaptic component of expression. BDNF-dependent forms of LTP also require activation of L-type voltage-gated calcium channels. One form of LTP with presynaptic expression, theta burst LTP, is thought to be of particular behavioral importance. Using restricted genetic deletion to selectively disrupt BDNF production in either the entire forebrain (CA3 and CA1) or in only the postsynaptic CA1 neuron, we localize the source of BDNF required for LTP to presynaptic neurons. These results suggest that long-term synaptic plasticity has distinct presynaptic and postsynaptic modules. Release of BDNF from CA3 neurons is required to recruit the presynaptic, but not postsynaptic, module of plasticity.     

Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice

Protein tyrosine phosphatase delta (PTPdelta) is a receptor-type PTP expressed in the specialized regions of the brain including the hippocampal CA2 and CA3, B lymphocytes and thymic medulla. To elucidate the physiological roles of PTPdelta, PTPdelta-deficient mice were produced by gene targeting. It was found that PTPdelta-deficient mice were semi-lethal due to insufficient food intake. They also exhibited learning impairment in the Morris water maze, reinforced T-maze and radial arm maze tasks. Interestingly, although the histology of the hippocampus appeared normal, the magnitudes of long-term potentiation (LTP) induced at hippocampal CA1 and CA3 synapses were significantly enhanced in PTPdelta-deficient mice, with augmented paired-pulse facilitation in the CA1 region. Thus, it was shown that PTPdelta plays important roles in regulating hippocampal LTP and learning processes, and that hippocampal LTP does not necessarily positively correlate with spatial learning ability. To our knowledge, this is the first report of a specific PTP involved in the regulation of synaptic plasticity or in the processes regulating learning and memory.     

C-Type natriuretic peptide modulates pre- and postsynaptic properties in hippocampal area CA1 in vitro

The cGMP producing natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP) are widely distributed in the brain and are highly expressed in the hippocampal regions CA1-CA3. To date only limited functional data is available concerning the physiological effects of the peptide hormone in the hippocampus. Therefore, we were interested in how bath application of the peptide hormone might influence synaptic plasticity following high frequency stimulation (HFS). We found that CNP application decreased the population spike (PS) amplitude after HFS, thereby affecting long-term potentiation (LTP) in acute hippocampal slices. To investigate the molecular consequences of CNP application leading to a decrease in PS amplitude, we further analyzed the impact of the hormone on the number of presynaptic synapsin I clusters and number of postsynaptic AMPA receptor subunit GluR1 clusters as well as their co-localization in a primary hippocampal cell culture system. The observed pre-and postsynaptic effects after CNP stimulation of the cGMP pathway in hippocampal cell cultures may underlie the effect of the peptide hormone on LTP.     

Effect of the zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) on hippocampal mossy fiber calcium signals and on synaptic transmission

An important pool of chelatable zinc is present in the synaptic vesicles of mossy fiber terminals from hippocampal CA3 area, being zinc released following single or repetitive electrical stimulation. Previous studies have suggested different synaptic roles for released mossy fiber zinc, including the inhibition of presynaptic calcium and of postsynaptic N-methyl-D-aspartate (NMDA) and gamma amino-butyric acid (GABAA) receptors. The effect of endogenously released zinc on mossy fiber long-term potentiation (LTP) induction also is not yet established. We have investigated the effect of the permeant zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) on mossy fiber calcium and on synaptic transmission, before and during the application of LTP-inducing stimulation. We have found, using the calcium indicator Fura-2, that single and tetanically-evoked mossy fiber calcium signals are both enhanced in the presence of 20 microM TPEN, while the single field potentials are unaffected. As expected, no effect was observed on the single calcium signals or field potentials obtained at the CA3-CA1 synapses, from the CA1 area, which has a lower concentration of vesicular zinc. These results support the idea that at the hippocampal mossy fiber synapses, released zinc inhibits presynaptic calcium mechanisms. A higher concentration of TPEN (100 microM) significantly reduced mossy fiber synaptic transmission but did not prevent the induction of mossy fiber LTP, suggesting that zinc is not required for the formation of this form of LTP.     

(56)Fe-particle radiation reduces neuronal output and attenuates lipopolysaccharide-induced inhibition of long-term potentiation in the mouse hippocampus

Exposure to space radiation consisting of high-energy charged (56)Fe particles represents a significant health risk for astronauts. (56)Fe-particle radiation affects the synaptic plasticity of the hippocampus and alters its response to the experimental immunological stressor lipopolysaccharide (LPS). We previously showed in mice that 1 month after exposure to (56)Fe-particle radiation, the LPS-induced inhibition of hippocampal long-term potentiation (LTP) was significantly attenuated, resulting in seemingly normal LTP. In the current study, we investigated this phenomenon further at longer times postirradiation. We exposed mice to accelerated iron particles ((56)Fe; 600 MeV/nucleon; 1, 2, 4 Gy; brain only), and 1, 3, 6 or 12 months postirradiation we administered LPS. Four hours after the intraperitoneal LPS injection, we prepared hippocampal slices to measure synaptic excitability and plasticity between CA3-CA1 neurons. In unexposed mice, we confirmed that LPS inhibited LTP at all times. However, in mice exposed to 2 Gy, the LPS-induced LTP inhibition was attenuated and reversed to control values. Such reversal was evident at 1 and 3 months but not 6 and 12 months postirradiation. In addition, at 6 and 12 months postirradiation, we observed inhibition of population spike (PS) amplitudes at 4 Gy that correlated with decrements in dendritic potentials, suggesting synaptic damage. Our data show that (56)Fe-particle radiation affects the response of the hippocampus to an immunological stressor and that the alterations progress over time.     

Involvement of the GABAergic Septo-Hippocampal Pathway in Brain Stimulation Reward

The hippocampus is a structure related to several cognitive processes, but not very much is known about its putative involvement in positive reinforcement. In its turn, the septum has been related to instrumental brain stimulation reward (BSR) by its electrical stimulation with trains of pulses. Although the anatomical relationships of the septo-hippocampal pathway are well established, the functional relationship between these structures during rewarding behaviors remains poorly understood. To explore hippocampal mechanisms involved in BSR, CA3-evoked field excitatory and inhibitory postsynaptic potentials (fEPSPs, fIPSPs) were recorded in the CA1 area during BSR in alert behaving mice. The synaptic efficiency was determined from changes in fEPSP and fIPSP amplitudes across the learning of a BSR task. The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs. Additionally, we evaluated CA1 local field potentials (LFPs) during a preference task, comparing 8-, 20-, and 100-Hz trains of septal BSR. We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma. These results were replicated by intrahippocampal injections of a GABA_B antagonist. Thus, the GABAergic septo-hippocampal pathway seems to carry information involved in the encoding of reward properties, where GABA_B receptors seem to play a key role. With regard to the dorsal hippocampus, fEPSPs evoked at the CA3-CA1 synapse seem to reflect the BSR learning process, while hippocampal rhythmic activities are more related to reward properties.     

高脂饲养青春期大鼠电击回避反应和海马CA3区场电位的改变

目的：观察高脂饲养至青春期的大鼠对电击回避反应和海马CA3区实时局部场电位变化。方法：断乳1周幼鼠改用基础饲料和高脂饲料分别喂养4周至青春期,分为基础饲料组（BF组）和高脂饲料组（HFD组）,Y型迷宫电击回避训练方法,记录2组大鼠电击回避达学会标准的相关参数,同时无线遥测大鼠达标时海马CA3区实时局部场电位。结果：与BF组大鼠比较,HFD组大鼠体重明显增加,Y型迷宫电击回避训练1~2 d大鼠达标百分率、电击回避达标各项指标均略优于BF组;双侧海马CA3区局部场电位节律出现去同步化快波改变,右侧海马CA3区出现了θ波和γ 1波百分比的同步性增加,但无θ~γ 1波相位-振幅耦合出现。结论：幼年期短期高脂饮食至青春期的大鼠,尽管体重较基础饲料大鼠增加,但未见Y型迷宫电击回避反应能力和海马依赖性空间认知功能的减退。     

Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice

Olfactory bulbectomized (OBX) mice showed significant impairment of learning and memory-related behaviors 14 days after olfactory bulbectomy, as measured by passive avoidance and Y-maze tasks. We here observed a large impairment of hippocampal long-term potentiation (LTP) in the OBX mice. Concomitant with decreased acetylcholinesterase expression, protein kinase C (PKC)alpha autophosphorylation and NR1(Ser-896) phosphorylation significantly decreased in the hippocampal CA1 region of OBX mice. Both PKCalpha and NR1(Ser-896) phosphorylation significantly increased following LTP in the control mice, whereas increases were not observed in OBX mice. Like PKC activities, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in the hippocampal CA1 region of OBX mice as compared with that of control mice. In addition, increased CaMKII autophosphorylation following LTP was not observed in OBX mice. Finally, the impairment of CaMKII autophosphorylation was closely associated with reduced pGluR1(Ser-831) phosphorylation, without change in synapsin I (site 3) phosphorylation in the hippocampal CA1 region of OBX mice. Taken together, in OBX mice NMDA receptor hypofunction, possibly through decreased PKCalpha activity, underlies decreased CaMKII activity in the post-synaptic regions, thereby impairing LTP induction in the hippocampal CA1 region. Both decreased PKC and CaMKII activities with concomitant LTP impairment account for the learning disability observed in OBX mice.     

Zinc signaling in the hippocampus and its relation to pathogenesis of depression

Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons. Zn(2+) serves as a signal factor in both the extracellular and intracellular compartments. Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of hippocampal function, i.e., cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress. We propose that corticosterone-mediated increase in postsynaptic Zn(2+) signal, which is induced by acute stress, changes hippocampal function and then is possibly a risk factor under chronic stress circumstances to induce depressive symptoms.     

Low Dose ZD7288 Attenuates the Ischemia/Reperfusion-Induced Impairment of Long-Term Potentiation Induction at Hippocampal Schaffer Collateral-CA1 Synapses

Focal cerebral ischemia can impair the induction of activity-dependent long-term potentiation (LTP) in the hippocampus. This impairment of hippocampal synaptic plasticity can be caused by excitotoxicity and subsequent perturbation of hippocampal LTP-relevant transmitter systems, which include NR2B and PSD-95. It has been suggested that hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels may play an important role in the control of membrane excitability and rhythmic neuronal activity. Our previous study has indicated that the selective HCN channel blocker ZD7288 can produce a dose-dependent inhibition of the induction of LTP at the Schaffer collateral-CA1 synapse of hippocampus by reducing the amount of glutamate released. It has also been demonstrated that ZD7288 can protect against neuronal injury caused by oxygen glucose deprivation. In the present study, we investigated the effect of ZD7288 on the induction of activity-dependent LTP and the expression of NR2B and PSD-95 after focal cerebral ischemia/reperfusion injury. The results showed that the induction of LTP was significantly impaired and the levels of NR2B and PSD-95 mRNA and protein were markedly decreased in the CA1 region of hippocampus following focal cerebral ischemia/reperfusion injury. Administration of low dose ZD7288 (0.25 μg) at 30 min and 3 h after the onset of ischemia attenuated the impairment of LTP induction and alleviated the NR2B and PSD-95 mRNA and protein down-regulation commonly induced by cerebral ischemia/reperfusion injury. These results suggest that low dose ZD7288 can ameliorate the ischemia/reperfusion-induced impairment of synaptic plasticity in the hippocampal CA1 region.