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To test the feasibility that whole body exposure to structurally matched, physiologically patterned magnetic fields could reduce cellular injury within specific regions of the brain, young rats were seized with lithium and pilocarpine and then exposed to a sham field or to one of three computer-generated magnetic field patterns. They were digitized equivalents of the pulsed patterns of electric current known to produce long-term potential (LTP) in slices of hippocampus or entorhinal cortices. Histological analyses of their brains as adults indicated the earlier exposure to the LTP-patterned fields produced a robust reduction of damage within the primary and association areas of the right temporal cortices and the CA1/CA2 hippocampal fields. The results suggest physiologically patterned magnetic fields could be employed to target specific nuclei anywhere within the brain by matching intrinsic activity.

Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.

Previous investigations have demonstrated that electroacupunctural stimulation can ameliorate primary and secondary symptoms such as peripheral neuropathy and diabetic encephalopathy in diabetic rats. In this study, we investigated whether electroacupuncture could improve learning and memory which was typically impaired in diabetic rats with cerebral ischemia. Furthermore, we investigated the mechanisms underlying its effects using passive avoidance test, active avoidance test, Morris water maze and electrophysiology. Electroacupuncture increased the step-down latency in passive avoidance test and accurate rate in active avoidance test, decreased the escape latency in Morris water maze. After electroacupuncture treatment, the long-term potentiation (LTP) impaired by both diabetes and cerebral ischemia was restored significantly. These results suggest that electroacupuncture can ameliorate learning and memory capacity impaired by hyperglycemia and ischemia. LTP plays a very important role in this beneficial effect.

The involvement of group I metabotropic glutamate receptors (mGluRs) and ryanodine receptors was investigated in the induction of LTP induced either by application of one standard high frequency stimulation (HFS) or by strong multiple HFS in the medial perforant path to granule cell synapse of the rat dentate gyrus. Whilst a standard brief HFS induced LTP close to 50%, strong stimulation consisting of multiple HFS induced a much larger LTP. mGluR5 was found to be partially involved in the induction of the enhanced LTP induced by the strong HFS but not in the standard LTP induced by the brief HFS. Thus the mGluR5 antagonists LY341495 and MPEP partially inhibited the induction of LTP induced by strong HFS but did not inhibit LTP induced by a standard HFS. Ryanodine was found to partially inhibit LTP induced by the strong HFS but not to inhibit the standard LTP induced by the brief HFS, demonstrating the involvement of Ca-induced Ca release from ryanodine-sensitive Ca stores in the former. These studies demonstrate that the large amplitude LTP induced by strong stimulation involves additional mechanisms to the LTP induced by brief HFS, in particular involving activation of mGluR5 and RyR-sensitive Ca stores.

Lifelong calorie restriction is the only known intervention that has been shown to consistently increase life span and reduce the effects of aging on the brain. Given the difficulties of replicating lifelong calorie restriction within human populations, we have sought to assess the effects of short-term adult-onset calorie restriction upon acute excitotoxic insults in the rat hippocampus. Adult animals (approximately 6 months of age) underwent calorie restriction (alternate day feeding) for 7-10 weeks. Utilizing both electrophysiological and immunocytochemical techniques, we report that calorie restriction had no effect upon long-term potentiation (LTP), a measure of neuronal function. In control animals, application of kainic acid (20 microM) resulted in only 35% recovery of CA1 population spikes post-insult. However calorie-restricted animals showed significantly improved recovery after kainic acid treatment (64%). This data was supported by immunocytochemical studies which noted widespread loss of microtubule-associated protein (MAP 2) immunoreactivity in control slices following treatment with kainic acid; however MAP 2 staining was preserved in the CA1 and CA3 regions of calorie-restricted animals. Interestingly there was no significant difference in the recovery of population spikes between groups when slices were treated with N-methyl-d-aspartate (15 microM). We conclude that short-term adult-onset calorie restriction does not alter normal neuronal function and serves to protect the hippocampus from acute kainic acid excitotoxicity.

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory impairments. We have previously demonstrated the inhibition of long-term potentiation (LTP), a recognised model for memory, in the dentate gyrus region of the rat hippocampus, by interleukin-18. We have also previously shown that the inhibitory effect of TNF-alpha on LTP can be attenuated by inhibitors of metabotropic glutamate receptors (mGluRs). We therefore went on to investigate the effects of the mGluR antagonists MPEP and MTPG on the effect of IL-18 on LTP in the rat dentate gyrus in vitro. Recordings of field excitatory post-synaptic potentials (EPSPs) were made from the medial perforant path of rat hippocampal slices. IL-18 (100 ng/ml) applied for 20 min before-HFS had no significant effect on baseline EPSPs but significantly impaired LTP (IL-18 LTP 116+/-9%, versus control LTP 163+/-6% 1h post-tetanus, P<0.001, n=5). Perfusion of the mGluR5 specific antagonist MPEP (5 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but significantly attenuated the inhibitory effect of IL-18 on LTP at 30 min but not 1h (177+/-2% and 138+/-8%, respectively, compared to controls; n=5). Perfusion of the group II mGluR antagonist MTPG (50 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but was found to significantly reverse the inhibitory effect of IL-18 on LTP at 1h (164+/-6% compared to IL-18 alone, n=5). This study provides novel evidence of the involvement of mGluRs in the IL-18 mediated inhibition of LTP.

Nicotinic acetylcholine receptors (nAChR) are widely expressed throughout the nervous system, are involved in some fast excitatory neurotransmission, and play an important role in modulating the release of several neurotransmitters, including the major excitatory and inhibitory neurotransmitters, glutamate and GABA. We used a recently characterised alpha4beta2 nAChR subunit selective partial agonist, TC-2559, to study the effect of alpha4beta2 nAChR activation on synaptic plasticity in the medio-dorsal perforant pathway input to the dentate gyrus, in the intact nervous system in vivo. We show for the first time, that the selective activation of alpha4beta2 containing nAChR can reduce the level of long-term potentiation (LTP) induced by high frequency stimulation, an effect that was reversed by the selective antagonist, dihydro-beta-erythroidine (DbetaHE). This modulator role of nAChRs is in contrast to previous findings that used broad spectrum agonists, highlighting the complex actions of nicotine.

Suppression of rapid eye movement sleep (REMS) in developing animals has both anatomical and physiological consequences. We have recently shown that initiating REMS deprivation (REMSD) prior to the end of the critical period in young rats delays termination of the critical period (CP) in visual cortex, and, consequently, the synaptic plasticity mechanisms that support a developmentally regulated form of long-term potentiation (LTP) are maintained in an immature state [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. In CP animals, high-frequency, theta burst stimulation (TBS) directed at the white matter (WM) below visual cortex produces LTP in the post-synaptic cells in layer II/III (LTPWM-III). However, LTPWM-III can be induced in cortical tissue taken from REMS-deprived animals for up to a week beyond the usual end of the CP [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. Further, in post-CP, adolescent animals (as late as postnatal day 60), REMSD appears to unmask synaptic plasticity mechanisms that allow for production of developmentally regulated LTPWM-III [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. It has been proposed that REMSD's effects on production of LTPWM-III result from a reduction in efficiency of the inhibitory mechanisms thought to precipitate termination of the CP of brain development [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. In this study we tested the hypothesis that low-frequency stimulation (LFS) of the fibers of the WM, which usually produces the related form of synaptic plasticity, long-term depression (LTD), will also reflect the reduction in inhibitory tone. We report here that LFS protocols, which in normally sleeping, adolescent rats usually produce either LTD or no change in response magnitude, in REMS-deprived, adolescent rats are more likely to produce LTP.

In deep cerebellar nuclei (DCN) neurons, inhibitory postsynaptic currents (IPSCs) undergo long-term depression (LTD) following a 10-Hz stimulation, and long-term potentiation (LTP) after a 100 Hz stimulation of the inputs. Whole-cell recordings were made from DCN neurons and changes in IPSC sensitivity to diazepam after LTD and LTP investigated. Diazepam enhanced the evoked IPSC amplitude by 45% in controls and after LTD induction. However, after LTP induction, diazepam increased the IPSC by only 16%. Diazepam increased THIP response by 34% in controls, but by only 4% after LTP. These results suggest that during LTP the diazepam sensitive GABAA receptor sub-units undergo changes.

The pineal product melatonin that acts on specific melatonin receptors has been implicated in pathobiological mechanisms of neuropsychiatric disorders including Alzheimer's disease. We used mice lacking melatonin MT(2) receptors (MT(2) knockouts) to investigate the role of these receptors in synaptic plasticity and learning-dependent behavior. In field CA1 of hippocampal slices from wild-type mice, theta burst stimulation induced robust and stable long-term potentiation that was smaller and decremental in slices from MT(2) knockouts. Tested in an elevated plus-maze on two consecutive days, wild-type mice showed shorter transfer latencies to enter a closed arm on the second day; this experience-dependent behavior did not occur in MT(2) knockouts. These results suggest that MT(2) receptors participate in hippocampal synaptic plasticity and in memory processes.

The subiculum plays a key role in processing neuronal information from the hippocampus to different cortical and subcortical brain regions. The subicular projections to the nucleus accumbens and the prefrontal cortex have received increasing attention, as alterations of their activity seem to be involved in schizophrenia. Phencyclidine and other non-competitive antagonists of NMDA receptors (such as ketamine and MK-801) induce psychotic effects in humans that closely resemble the positive, negative and cognitive symptoms of schizophrenia. Using the MK-801 model of psychosis, we investigated the time course of alterations of synaptic transmission and plasticity at CA1-subiculum synapses of hippocampal brain slices 4 h, 24 h and 4 weeks after MK-801 treatment. We report here that systemic application of MK-801 causes a facilitation of LTP at CA1-subiculum synapses 24 h after treatment as compared with control LTP. Four weeks after MK-801 treatment, the magnitude of LTP reversed to control values. The priming of LTP 24 h after systemic application of MK-801 suggest a new form of metaplasticity that sheds light on the delayed facilitating effect of this drug on synaptic efficacy.

The molecular and cellular mechanisms underlying the cognitive deficiency of senescence-accelerated mouse prone/8 (SAMP8) have been attributed to many pathological changes in neurons. Recently, increasing evidence has shown that astrocytes, by mean of d-serine, involve in the process of synaptic transmission. Here we reported that the long-term potentiation (LTP) in CA1 area of hippocampal slices prepared from 2-, 6- and 12-month-old SAMP8 significantly decreased with age. Meanwhile, the LTP in the slices of 6- and 12-month-old mice markedly decreased below that of the age-matched normal strain SAMR1. Supplement with exogenous d-serine, a main product of astrocytes and a coagonist at the "glycin-binding" site of N-methyl-d-aspartate (NMDA) receptors, not only directly enhanced the deficient LTP but also rescued the abolished LTP by d-amino acid oxidase (DAAO) in slices from 12-month-old SAMP8. This ameliorative effect of d-serine was inhibited by either AP-V or 5,7-dichlorokynurenic acid (DCKA). These results suggest that absence of d-serine or dysfunction of the astrocytes possibly was one of mechanisms underlying the decrease of NMDA receptor-dependent LTP and cognition in aged SAMP8.

In Mg2+ -free aCSF, bursting discharges were induced in the posterior telencephalon of zebrafish following an electrical stimulation of the anterior telencephalon. The bursting discharges were partially reduced by CNQX (10 microM), an AMPA receptor antagonist, and the remaining activity was completely blocked by an additional treatment of APV (50 microM), an NMDA receptor antagonist. Long-term potentiation that lasted more than 1 h was also induced after 20 min of perfusion with KCl (10 mM). The degree of KCl-induced long-term potentiation (K-LTP) was reduced when a concomitant electrical stimulation was not delivered during a KCl perfusion. K-LTP was blocked by APV (50 microM) but not by nifedipine (1 microM), an L-type Ca2+ channel blocker. Furthermore, K-LTP was not induced in the presence of a broad spectrum inhibitor for protein kinases, H-7 (10 microM). These results suggest that NMDA receptors and protein kinases play important roles in the synaptic plasticity of the zebrafish brain.

Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 microM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain.

We examined synaptic plasticity in the optic tectum of rainbow trout by extracellular recordings. We found that the field-excitatory postsynaptic potential in the retinotectal synapses was potentiated by repetitive stimuli of 1.0 Hz for 20 s to the retinotectal afferents. The long-term potentiation (LTP) developed slowly, and was maintained for at least 2 h. Applications of an antagonist for N-methyl-D-aspartic acid (NMDA) receptors or Mg2+ -free saline showed that activation of NMDA receptors was required to form the LTP beyond the induction period. The present findings indicate that presynaptic stimulation in the retinotectal synapses causes LTP mediated by NMDA receptors in the optic tectum of rainbow trout.

Human apolipoprotein E (apoE) comprises three isoforms, apoE2, apoE3 and apoE4, and apoE4 has been reported as a risk factor of Alzheimer's disease (AD). One of the clinical symptoms of AD is disorder of memory that has been suggested to be related with synaptic plasticity such as long-term potentiation (LTP). Here, we show the enhancement of hippocampal LTP at younger age in knock-in mice lacking mouse apoE, but instead expressing human apoE4. The enhancement of LTP in apoE4 knock-in mice is age-dependent, and it disappears in adult apoE4 knock-in mice. In apoE3 knock-in mice LTP is unaltered, thus human apoE4, but not apoE3, specifically modulates synaptic plasticity at younger age. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 knock-in mice, postsynaptic functional modification of LTP through lipid homeostasis is suggested. ApoE4 knock-in mice would be a useful animal model of human apoE4 carriers, and our finding that LTP is enhanced in younger apoE4 knock-in mice is in accord with the previous report showing higher intelligence in young human apoE4 carriers.