Long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are forms of synaptic plasticity that have been studied extensively and are thought to contribute to learning and memory. The reversal of LTP, known as depotentiation (DP) has received far less attention however, and its role in behavior is also far from clear. Recently, deficits in depotentiation have been observed in models of schizophrenia, suggesting that a greater understanding of this form of synaptic plasticity may help reveal the physiological alterations that underlie symptoms experienced by patients. This review therefore seeks to summarize the current state of knowledge on DP, and then put the deficits in DP in models of disease into this context.
Depression ; Humans ; Learning ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Memory ; Neuronal Plasticity ; Plastics ; Schizophrenia ; Synaptic Transmission

OBJECTIVETo study the roles of protein synthesis inhibitors in long-term potentiation(LTP) and depotentiation(DP) in hippocampal CA1 region of adult rats.

METHODSStandard extracellular recording technique was used to record field EPSP(fEPSP) evoked by Schaffer collateral stimulation from the CA1 subfield of adult rat hippocampal slices. Paired-pulse low-frequency stimulation(PP-LFS) or high-intensity paired-pulse low-frequency stimulation(HI-PP-LFS) was delivered to induce depotentiation 2 h after LTP induction induced by six theta-burst stimulations. Protein synthesis inhibitors were applied before and after LTP induction to study their roles in LTP and DP in hippocampal CA1 region of adult rats.

RESULTSWhen HI-PP-LFS was applied at 2 h after LTP induction, the depotentiation was induced. The mean fEPSP slopes reduced from 346.2%±26.3% to 207.1%±21.6%. This depotentiation was named as partial LTP depotentiation and maintained at least for 30 min. The percentage of depotentiation was 59.81%. Application of protein synthesis inhibitors, anisomycin and cycloheximide prior to tetanus resulted in smaller LTP compared to control group, and almost complete depotentiation was induced by HI-PP-LFS. With application of protein synthesis inhibitors anisomycin and cycloheximide 90 min after LTP induction, HI-PP-LFS still induced partial LTP depotentiation. However, there was no significant difference in the percentage of depotentiation between this group and control group.

CONCLUSIONHI-PP-LFS partially reverses late phase LTP. When protein synthesis inhibitors are applied prior to tetanus, LTP amplitude is markedly reduced, and HI-PP-LFS completely reverses late-phase LTP. Application of protein synthesis inhibitors after LTP induction does not significantly affect either the amplitude or depotentiation of LTP.

Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction.
Animals ; Aquaporin 4 ; physiology ; Hippocampus ; physiology ; Humans ; Learning ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Memory ; Neuronal Plasticity

Animals ; Brain ; physiology ; Extinction, Psychological ; physiology ; Humans ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Neural Pathways ; physiology ; Neuronal Plasticity ; Neurons ; physiology ; Receptors, AMPA ; physiology

Previous reports suggested that a low-frequency stimulus (LFS) of 1~2 Hz (600~900 pulses) induced a homosynaptic long-term depression (LTD) of synaptic efficacy in the hippocampal CA1 area of young rats (< 4-week old). However, these stimulation protocols often failed to induce LTD in the adult CA1 hippocampus. In the present study, we examined the effects of two novel tetanus patterns on LTD induction in adult rat hippocampal slices. We determined that these novel stimulation protocols induced LTD in the adult hippocampus, and that the characteristics of induced LTD were parameter-specific, including latency (period from the end of tetanus to a beginning of LTD) and the amplitude of LTD. These results suggest that LFS with certain patterns can induce LTD in the CA1 area of adult rat hippocampal slices, and that the multi-trains of 2-Hz protocol provided more effective response than the 5-Hz protocol.
Animals ; CA1 Region, Hippocampal ; physiology ; Electric Stimulation ; In Vitro Techniques ; Long-Term Synaptic Depression ; physiology ; Male ; Rats ; Rats, Sprague-Dawley

The technique of extracellular recording was used and the changes in the slope of field excitatory postsynaptic potential (S-EPSP) and the amplitude of population spike (A-PS) were observed when homosynaptic long-term depression (LTD) was induced by low-frequency stimulation (LFS) in the CA1 region of rat hippocampal slices. After LFS of 900 pulses at 1 Hz was delivered, S-EPSP and A-PS were reduced by 35.4 +/- 5.3% and 68.0 +/- 7.2%, respectively. When LFS of 450 pulses at 1 Hz was delivered, S-EPSP and A-PS were reduced by 14.3 +/- 2.3% and 36.8 +/- 6.7%, respectively. In both groups, the change in A-PS was significantly greater than that in S-EPSP (P<0.01). The changes in both indexes in the group of 900 pulses were greater than those in the group of 450 pulses (P<0.05). High Mg(2+) (4 mmol/L) could attenuate the synaptic transmission, but did not affect the induction of LTD. In the high Mg(2+) medium, the change in A-PS induced by LFS was also markedly greater than that in S-EPSP (P<0.01). These results indicate that the level of homosynaptic LTD induced by LFS is dependent not only on the numbers of pulses of LFS delivered, but also on the selection of evaluating index.
Animals ; Electric Stimulation ; Excitatory Postsynaptic Potentials ; physiology ; Hippocampus ; physiology ; In Vitro Techniques ; Long-Term Synaptic Depression ; Male ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission ; physiology

The purpose of this study was to explore the effects of calcitonin gene-related peptide (CGRP) on the long-term depression (LTD) of hippocampus in mice. Sixty C57BL/6J mice (30 days old) were randomly divided into control group, three CGRP (50, 100, and 200 nmol/L) groups, CGRP + CGRP group and CGRP + APV group (10 mice for each group). The effects of exogenous application of different concentrations of CGRP on synaptic plasticity and LTD in hippocampus of mice were detected by in vitro recording of local field potential. The results showed that higher doses (100 and 200 nmol/L) of CGRP significantly enhanced the induction of LTD in the hippocampus. Moreover, CGRP increased the magnitude of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents. The above-mentioned effects of CGRP were blocked by either CGRP selective antagonist CGRP or NMDA receptor antagonist APV. These results suggest that CGRP can dose-dependently enhance the induction of LTD in hippocampus of mice, and the underlying mechanism involves the mediation of NMDA receptor function.
Animals ; Calcitonin Gene-Related Peptide ; pharmacology ; Hippocampus ; drug effects ; Long-Term Synaptic Depression ; drug effects ; Mice ; Mice, Inbred C57BL ; Random Allocation

Nitric oxide (NO) is a gaseous messenger that plays a role in neurotransmission, long term potentiation, depression and cerebral blood flow. Increases in intracellular calcium levels activate the enzyme NOS, and the NO released then diffuse to adjacent cells and activate guanylate cyclase. NO mediates the increase in cerebral blood flow during seizure activity. Therefore, the present study was aimed to investigate the change of NOS and calcium binding proteins in the rat cerebral cortex following seizure. Rats were injected with kainate (KA) and killed at 6 hours, 1, 3, 5 and 10 days after seizure. Expressional change of nNOS, calbindin D28k and parvalbumin was assessed by histochemistry, immunohistochemistry and microdensitometry in the rat brain. The intensity of the NADPH -d staining in rat cortical neurons showed a marked susceptibility to KA administration. At 6 hours and 3 days after seizure, the optical density of the NADPH -d staining was increased relative to the signal in saline treated control rats. At 5 and 10 days after seizure, the optical density of NADPH -d staining was not significantly different in most cortical regions compared to controls. In the hippocampus, the optical density of NADPH -d staining was highest at 5 days after seizure. The optical densities of calbindin D28k and parvalbumin positive neurons were various in the cerebral cortex, hippocampus and caudatoputamen during postseizure period. These results indicate that the calcium binding proteins investigated here are not essential for determining the activation of nNOS/NADPH -d positive neurons in the cerebral cortex and striatum.
Animals ; Brain* ; Calbindin 1 ; Calbindins ; Calcium* ; Calcium-Binding Proteins ; Carrier Proteins* ; Cerebral Cortex ; Depression ; Guanylate Cyclase ; Hippocampus ; Immunohistochemistry ; Kainic Acid ; Long-Term Potentiation ; NADP* ; Neurons* ; Nitric Oxide ; Rats* ; Seizures* ; Synaptic Transmission

Administration of kainate (KA) results in the induction of epileptiform activity and limbic motor seizures. Nitric oxide (NO) is a gaseous messenger that plays a role in neural transmission, long term potentiation, depression and cerebral blood flow. NO is formed by NO synthase (NOS) from arginine. NO mediates the increase in cerebral blood flow during seizure activity. However, the production site of NO has not been clearly defined. Recent report showed that constitutive NOS may be induced under certain conditions. Therefore, the present study was aimed to investigate the change of NOS and calbindin D28k in the rat cerebral cortex following seizure. Rats were injected with KA and killed at 6 hours, 1, 3, 6 and 12 days after seizure. Expressional change of nNOS and calbindin D28k was assessed by histochemistry, immunohistochemistry and RT-PCR in the rat brain. Induced NADPH-d positive neurons were observed in the cerebral cortex of 1, 3, 6 and 12 days after seizure and found in specific cortical areas, such as motor cortex, somatosensory cortex, auditory cortex, visual cortex, ectorhinal cortex and perirhinal cortex. The level of nNOS mRNA increased at 1, 3, 6 and 12 days after seizure compared with control group. Induced calbindin D28k positive neurons were observed in motor cortex and somatosensory cortex 1 and 3 days after seizure. The level of calbindin D28k mRNA in the cerebral cortex was slightly decreased at 1 day after seizure. Therefore, in this study, the induced NADPH-d, calbindin D28k positive neurons and upregulated NADPH-d positive neurons may influence the cerebral blood flow and neuronal activity in the cerebral cortex during post-seizure period.
Animals ; Arginine ; Auditory Cortex ; Brain ; Calbindin 1* ; Calbindins* ; Cerebral Cortex* ; Depression ; Immunohistochemistry ; Kainic Acid ; Long-Term Potentiation ; Motor Cortex ; Neurons* ; Nitric Oxide ; Nitric Oxide Synthase ; Rats* ; RNA, Messenger ; Seizures ; Somatosensory Cortex ; Synaptic Transmission ; Visual Cortex

Previous reports suggested that a novel stimulus pattern of multi-train stimulus at low-frequency (2-Hz or 5-Hz) could induce stable long-term depression (LTD) in the CA1 area of adult rat hippocampus. In the present study, in order to determine the mechanism in LTD induced by the two novel tetanus patterns, changes in the population spikes (PS) in the hippocampal CA1 area of adult rats following the multi-train stimulus in the presence of AP5 [antagonist of N-methyl-D-aspartate receptors (NMDARs)] or MCPG [antagonist of type I/II metabotropic glutamate receptors (mGluRs)] were recorded. The results showed that both AP5 and MCPG inhibited the LTD induced by 2-Hz multi-train stimulus. The mean amplitude of population spikes (PSA) normalized to the baseline was (96.0±3.5)% after applying AP5 (n=10) and (95.7±4.1)% after applying MCPG (n=8), respectively, measured at 20 min post-tetanus. While 5-Hz multi-train tetanus failed to induce LTD in the presence of MCPG. The mean PSA was (73.6±4.4)% (n=10) and (98.2±8.9)% (n=8) in the presence of AP5 and MCPG, respectively, measured at 35 min post-tetanus. So it is suggested that LTD induced by 2-Hz multi-train tetanus involves co-activation of NMDARs and mGluRs, while LTD induced by 5-Hz multi-train tetanus is only related to activation of mGluRs.
2-Amino-5-phosphonovalerate ; pharmacology ; Animals ; CA1 Region, Hippocampal ; physiology ; Glycine ; analogs & derivatives ; pharmacology ; Long-Term Synaptic Depression ; Rats ; Receptors, Metabotropic Glutamate ; antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors