Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

Melatonin protects against amyloid‐β‐induced impairments of hippocampal LTP and spatial learning in rats

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, leads to progressive loss of memory and cognitive deficits. Amyloid‐β protein (Aβ) in the brain is thought to be the main cause of memory loss in AD. Melatonin, an indole hormone secreted by the pineal gland, has been reported to produce neuroprotective effects. We examined whether melatonin could protect Aβ‐induced impairments of hippocampal synaptic plasticity, neuronal cooperative activity, and learning and memory. Rats received bilateral intrahippocampal injection of Aβ1‐42 or Aβ31‐35 followed by intraperitoneal application of melatonin for 10 days, and the effects of chronic melatonin treatment on in vivo hippocampal long‐term potentiation (LTP) and theta rhythm and Morris water maze performance were examined. We showed that intrahippocampal injection of Aβ1‐42 or Aβ31‐35 impaired hippocampal LTP in vivo, while chronic melatonin treatment reversed Aβ1‐42‐ or Aβ31‐35‐induced impairments in LTP induction. Intrahippocampal injection of Aβ31‐35 impaired spatial learning and decreased the power of theta rhythm in the CA1 region induced by tail pinch, and these synaptic, circuit, and learning deficits were rescued by chronic melatonin treatment. These results provide evidence for the neuroprotective action of melatonin against Aβ insults and suggest a strategy for alleviating cognition deficits of AD. Synapse 67:626–636, 2013 . © 2013 Wiley Periodicals, Inc.     

Neuron-Specific Expression of Tomosyn1 in the Mouse Hippocampal Dentate Gyrus Impairs Spatial Learning and Memory

Tomosyn, a syntaxin-binding protein, is known to inhibit vesicle priming and synaptic transmission via interference with the formation of SNARE complexes. Using a lentiviral vector, we specifically overexpressed tomosyn1 in hippocampal dentate gyrus neurons in adult mice. Mice were then subjected to spatial learning and memory tasks and electrophysiological measurements from hippocampal slices. Tomosyn1-overexpression significantly impaired hippocampus-dependent spatial memory while tested in the Morris water maze. Further, tomosyn1-overexpressing mice utilize swimming strategies of lesser cognitive ability in the Morris water maze compared with control mice. Electrophysiological measurements at mossy fiber-CA3 synapses revealed impaired paired-pulse facilitation in the mossy fiber of tomosyn1-overexpressing mice. This study provides evidence for novel roles for tomosyn1 in hippocampus-dependent spatial learning and memory, potentially via decreased synaptic transmission in mossy fiber-CA3 synapses. Moreover, it provides new insight regarding the role of the hippocampal dentate gyrus and mossy fiber-CA3 synapses in swimming strategy preference, and in learning and memory.     

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits,biochemical changes,and hippocampal synaptic plasticity in an animal model of depression

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression‐associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression‐associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression‐induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long‐term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight‐arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression‐associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. © 2014 Wiley Periodicals, Inc.     

Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring

Clinical studies demonstrate that prenatal stress causes cognitive deficits and increases vulnerability to affective disorders in children and adolescents. The underlying mechanisms are not yet fully understood. Here, we reported that prenatal stress (10 unpredictable, 1 s, 0.8 mA foot shocks per day during gestational days 13-19) impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in hippocampal CA1 region in slices of the prenatal stressed offspring (5 weeks old). Cross-fostering neonate offspring by the prenatal stressed or control mothers did not change the effects of prenatal stress on the hippocampal LTP and LTD. Furthermore, prenatal stress enhanced the effects of acute stress on the hippocampal LTP and LTD and impaired spatial learning and memory in the Morris water maze in the young rat offspring. Therefore, prenatal stress alters synaptic plasticity and enhances the effects of acute stress on synaptic plasticity in the hippocampus, which may be the mechanism for the impaired spatial learning and memory in young rat offspring.     

Enhanced hippocampal neuronal excitability and LTP persistence associated with reduced behavioral flexibility in the maternal immune activation model of schizophrenia

Individuals with schizophrenia display a number of structural and cytoarchitectural alterations in the hippocampus, suggesting that other functions such as synaptic plasticity may also be modified. Altered hippocampal plasticity is likely to affect memory processing, and therefore any such pathology may contribute to the cognitive symptoms of schizophrenia, which includes prominent memory impairment. The current study tested whether prenatal exposure to infection, an environmental risk factor that has previously been associated with schizophrenia produced changes in hippocampal synaptic transmission or plasticity, using the maternal immune activation (MIA) animal model. We also assessed performance in hippocampus‐dependent memory tasks to determine whether altered plasticity is associated with memory dysfunction. MIA did not alter basal synaptic transmission in either the dentate gyrus or CA1 of freely moving adult rats. It did, however, result in increased paired‐pulse facilitation of the dentate gyrus population spike and an enhanced persistence of dentate long‐term potentiation. MIA animals displayed slower learning of a reversed platform location in the water maze, and a similarly slowed learning during reversal in a spatial plus maze task. Together these findings are indicative of reduced behavioral flexibility in response to changes in task requirements. The results are consistent with the hypothesis that hippocampal plasticity is altered in schizophrenia, and that this change in plasticity mechanisms may underlie some aspects of cognitive dysfunction in this disorder. © 2013 Wiley Periodicals, Inc.     

Plasticity and metaplasticity of adult rat hippocampal mossy fibers induced by neurotrophin‐3

Changes in synaptic efficacy and morphology are considered as the downstream mechanisms of consolidation of memories and other adaptive behaviors. In the last decade, neurotrophin‐3 (NT‐3) has emerged as one potent mediator of synaptic plasticity. In the adult brain, expression of NT‐3 is largely confined to the hippocampal dentate gyrus (DG). Our previous studies show that application of high‐frequency stimulation (HFS) sufficient to elicit long‐term potentiation (LTP) at the DG‐CA3 pathway as well as acute intrahippocampal microinfusion of brain‐derived neurotrophin factor produce mossy fiber (MF) structural reorganization. Here, we show that intrahippocampal microinfusion of NT‐3 induces a long‐lasting potentiation of synaptic efficacy in the DG‐CA3 projection accompanied by an MF structural reorganization of adult rats in vivo. It is considered that the capacity of synapses to express plastic changes is itself subject to variation depending on previous experience; taking into consideration the effects of NT‐3 on MF synaptic plasticity, we thus used intrahippocampal microinfusion of NT‐3 to analyse its effects on functional and structural plasticity induced by subsequent MF‐HFS sufficient to induce LTP in adult rats, in vivo. Our results show that NT‐3 modifies the ability of the MF pathway to present subsequent LTP by HFS, and modifies the structural reorganization pattern. The modifications in synaptic efficacy and morphology elicited by NT‐3 at the MF‐CA3 pathway were blocked by the presence of a Trk receptor inhibitor (K252a). These findings support the idea that NT‐3 actions modify subsequent synaptic plasticity, a homeostatic mechanism thought to be essential for maintaining synapses in the adult mammalian brain.     

Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus.

Neonatal seizures are frequently associated with cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular region of the dentate gyrus in the hippocampus when studied as adults. The goal of this study was to determine the age of onset of cognitive dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal seizures and the relation of this cognitive impairment to mossy fiber sprouting and expression of glutamate receptors. Starting at postnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) and NMDA (NMDAR1) subreceptor expression at these same time points. Rats with neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular region of the dentate gyrus at P35. Our findings indicate that altered seizure susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal seizures will have to be initiated during, or shortly following, the seizures.     

Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity,anxiety, and memory deficits

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long‐term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety‐like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short‐term EE for 10 days can overcome restraint stress–induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short‐term EE on chronic stress–induced impaired LTP, working memory, and anxiety‐like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1‐LTP, increased anxiety‐like symptoms in elevated plus maze, and impaired working memory in T‐maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc.     

Chronic methamphetamine exposure produces a delayed,long‐lasting memory deficit

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long‐term deficits in short‐term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short‐term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short‐term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH‐exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short‐term as well as long‐term consequences of methamphetamine exposure. Synapse 67:245–257, 2013. © 2012 Wiley Periodicals, Inc.     

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

Using mice with a targeted disruption of the adenosine A1 receptor (A1R), we examined the role of A1Rs in hippocampal long-term potentiation (LTP), long-term depression (LTD), and memory formation. Recordings from the Shaffer collateral-CA1 pathway of hippocampal slices from adult mice showed no differences between theta burst and tetanic stimulation-induced LTP in adenosine A1 receptor knockout (A1R-/-), heterozygote (A1R+/-), and wildtype (A1R+/+) mice. However, paired pulse facilitation was impaired significantly in A1R-/- slices as compared to A1R+/+ slices. LTD in the CA1 region was unaffected by the genetic manipulation. The three genotypes showed similar memory acquisition patterns when assessed for spatial reference and working memory in the Morris water maze tasks at 9 months of age. However, 10 months later A1R-/- mice showed some deficits in the 6-arm radial tunnel maze test. The latter appeared, however, not due to memory deficits but to decreased habituation to the test environment. Taken together, we observe normal spatial learning and memory and hippocampal CA1 synaptic plasticity in adult adenosine A1R knockout mice, but find modifications in arousal-related processes, including habituation, in this knockout model.     

Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study

Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.     

The neuroprotection of Rattin against amyloid β peptide in spatial memory and synaptic plasticity of rats

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid β (Aβ) peptide‐induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aβ‐induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aβ31–35 on the spatial reference memory and in vivo hippocampal Long‐term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra‐hippocampal injection of Rattin effectively prevented the Aβ31–35‐induced spatial memory deficits and hippocampal LTP suppression in rats; the Aβ31–35‐induced activation of Caspase‐3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aβ31–35‐induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases‐3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aβ‐related cognitive deficits. © 2013 Wiley Periodicals, Inc.     

Long- and short-term plasticity at mossy fiber synapses on mossy cells in the rat dentate gyrus

Mossy cells give rise to the commissural and associational pathway of the dentate gyrus, and receive their major excitatory inputs from the mossy fibers of granule cells. Through these feed-back excitatory connections, mossy cells have been suggested to play important roles in both normal signal processing in learning and memory, as well as in seizure propagation. However, the nature of the activity-dependent modifications of the mossy fiber inputs to mossy hilar cells is not well understood. We studied the long- and short-term plasticity properties of the mossy fiber-mossy cell synapse, using the minimal stimulation technique in slices in whole cell recorded mossy cells retrogradely prelabeled with the fluorescent dye DiO from the contralateral dentate gyrus. Following tetanic stimulation, mossy fiber synapses showed significant NMDA receptor-independent long-term potentiation (LTP), associated with increased excitatory postsynaptic currents (EPSC) amplitude and decreased failure rates. Coefficient of variance and failure rate analyses suggested a presynaptic locus of LTP induction. Mossy fiber synapses on mossy cells also showed activity-dependent short-term modification properties, including both frequency-dependent facilitation (stimuli at higher frequencies evoked larger EPSCs with lower failure rates) and burst facilitation (each EPSC in a burst had a larger amplitude and higher probability of occurrence than the preceding EPSCs within the burst). The data show that mossy fiber-mossy cell synapses exhibit both long- and short-term plasticity phenomena that are generally similar to the mossy fiber synapses on CA3 pyramidal cells.     

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11–18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22–31) performed one two‐trial Y‐maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long‐term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine‐exposed juvenile offspring. The morphine group also showed poorer performance for the Y‐maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP‐spike potentiation. Then a loss of GABA‐containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy. © 2008 Wiley‐Liss, Inc.     

Cognitive dysfunction after experimental febrile seizures

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.     

Acute nicotine treatment prevents rem sleep deprivation‐induced learning and memory impairment in rat

Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long‐term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD‐induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg^?1 s.c.) twice a day. In the radial arm water maze (RAWM) task, 24‐ or 48‐h SD significantly impaired learning and short‐term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24‐ and 48‐h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD‐induced impairment of learning and STM and prevented SD‐induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity. © 2010 Wiley‐Liss, Inc.     

Late phase of long‐term potentiation in the mossy fiber—CA3 hippocampal pathway is critically dependent on metalloproteinases activity

Matrix metalloproteinases (MMPs) are known to play a pivotal role in remodeling of the extracellular matrix and have been implicated in synaptic plasticity, learning and memory. In hippocampus, inhibition of MMPs impairs the maintenance of long term plasticity in Schaeffer collateral‐CA1 (Sch/CA1) synapses while its effect on short term plasticity remains a matter of debate. Surprisingly little is known on the role of MMPs in other hippocampal synapses. In this study we have investigated the impact of a broad spectrum MMPs inhibitor, FN‐439 on synaptic transmission in mossy fiber‐CA3 (MF/CA3) synapses exhibiting profoundly different mechanism of long term potentiation (LTP) as well as robust short‐term plasticity, features that clearly distinguish them from the Sch/CA1 synapses. We report, that MMPs blockade before and up to 30 minutes after LTP induction resulted in a severe disruption of the late phase of tetanically induced LTP. However, LTP time course was not changed when FN439 was administered 60 minutes post LTP induction indicating that MMPs activity is required for the consolidation of the synaptic plasticity within a specific time window. The paired‐pulse facilitation ratio or post‐tetanic potentiation or burst‐like pattern of mossy fiber stimulation were not changed in the presence of FN‐439 administered for 15 minutes suggesting that temporal pattern of presynaptic transmitter release and, in general, the MF‐CA3 fidelity is not significantly affected by MMPs inhibition. We conclude that although the mechanisms of long‐term plasticity in MF/CA3 and in Sch/CA1 are profoundly different, MMPs play a crucial role in both pathways in the maintenance of LTP, which is believed to play an important role in learning and memory in the hippocampus. © 2010 Wiley‐Liss, Inc.     

Upstairs/downstairs revisited: spatial pretraining‐induced rescue of normal spatial learning during selective blockade of hippocampal N‐methyl‐d‐aspartate receptors

Spatial pretraining can enable spatial learning in another environment that ordinarily requires hippocampal N‐methyl‐d ‐aspartate (NMDA) receptor activity to become independent of that activity. This study explored further the circumstances in which this training‐induced ‘rescue’ of later learning in the presence of the NMDA receptor antagonist 2‐amino‐5‐phosphonovaleric acid (D‐AP5) can occur. D‐AP5 (0, 10, 20 and 30 mm in artificial cerebrospinal fluid) was infused continuously (0.5 μL/h, from a minipump) and bilaterally into the dorsal hippocampus during spatial‐reference‐memory training in a watermaze (4 trials/day, 8 days). This was preceded either by handling only or by identical spatial training in another watermaze in a separate laboratory with different extramaze cues. In naïve rats, D‐AP5 caused a dose‐related impairment in spatial reference memory acquisition that was significant at the lowest 5 nm /h infusion concentration. In pretrained rats, the dose–response function was shifted such that, in watermaze 2, spatial learning was normal at this low concentration, with a deficit at higher infusion concentrations. The induction of long‐term potentiation in the dentate gyrus in vivo was blocked at all D‐AP5 concentrations. Sensorimotor abnormalities sometimes seen with NMDA receptor antagonists were only apparent at the highest concentration. The implication of this paradoxical dissociation between hippocampal NMDA receptor‐dependent plasticity and spatial learning is discussed with reference to two rival hypotheses of the impact of pretraining.