Synaptic plasticity in the human dentate gyrus.
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Activity-dependent plasticity is a fundamental feature of most CNS synapses and is thought to be a synaptic correlate of memory in rodents. In humans, NMDA receptors have been linked to verbal memory processes, but it is unclear whether NMDA receptor-dependent synaptic plasticity can be recruited for information storage in the human CNS. Here we have for the first time analyzed different forms of synaptic plasticity in human hippocampus. In human subjects who show a morphologically intact hippocampus that is not the primary seizure focus, NMDA receptor-dependent long-term potentiation (LTP) and forskolin-induced long-lasting potentiation are readily induced at the perforant path-dentate gyrus synapse. In this group, long-term potentiation could be partially depotentiated by low-frequency stimulation. Because patients with a hippocampal seizure focus showed a marked reduction in verbal memory performance in previous studies, we asked whether synaptic plasticity is similarly affected by the presence of a hippocampal primary seizure focus. We found that the amount of potentiation induced by high-frequency stimulation or perfusion of forskolin is dramatically reduced in this patient group. In addition, low-frequency stimulation is not effective in inducing synaptic depression. In summary, we show that activity-dependent synaptic plasticity with properties similar to the rodent is available for information storage in the human hippocampus. Because both verbal memory processes and synaptic plasticity are impaired by a hippocampal seizure focus, we suggest that impaired synaptic plasticity may contribute to deficient declarative memory in human temporal lobe epilepsy. (+info)
Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase.
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Reactive oxygen species, including superoxide, generally are considered neurotoxic molecules whose effects can be alleviated by antioxidants. Different from this view, we show that scavenging of superoxide with an antioxidant enzyme is associated with deficits in hippocampal long-term potentiation (LTP), a putative neural substrate of memory, and hippocampal-mediated memory function. Using transgenic mice that overexpress extracellular superoxide dismutase (EC-SOD), a superoxide scavenger, we found that LTP was impaired in hippocampal area CA1 despite normal LTP in area CA3. The LTP impairment in area CA1 could be reversed by inhibition of EC-SOD. In addition, we found that EC-SOD transgenic mice exhibited impaired long-term memory of fear conditioning to contextual cues despite exhibiting normal short-term memory of the conditioning experience. These findings strongly suggest that superoxide, rather than being considered exclusively a neurotoxic molecule, should also be considered a signaling molecule necessary for normal neuronal function. (+info)
Misidentification syndromes related to face specific area in the fusiform gyrus.
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The "delusional misidentification syndromes" are a group of uncommon and varied disorders in which, in typical form, the patient thinks that a particular familiar person is someone else or a certain familiar place is a duplicate. Although first identified and considered a memory disorder by Pick, evidence in support of this has been difficult to identify. They have been most often seen in various psychotic and organic brain diseases but lesions have been generally diffuse although the right temporal lobe has been implicated. A patient was investigated who abruptly developed a disorder wherein she misidentified her husband as her deceased sister and claimed that her home was a duplicate of her real home that were typical of Fregoli syndrome and Pick's reduplicative paramnesia, respectively. A discrete area of brain damage, probably ischaemic, in this patient was seen on MRI in the anterior part of the right fusiform gyrus and a smaller area in the nearby anterior middle and inferior temporal gyri with associated parahippocampal and hippocampal atrophy. A high order nervous system function that is devoted to the identification of faces is located in the adjacent midportion of the fusiform gyrus and a similar locus for environmental scenes, termed the parahippocampal place area, is present in the bordering parahippocampal gyrus. The misidentification phenomena in this case can be explained by disruption of the connections of these highly specialised areas with the most anterior inferior and medial part of the right temporal lobe where long term memory and mechanisms for the retrieval of information that are required for the visual recognition of faces and scenes are stored. (+info)
Varying intertrial interval reveals temporally defined memory deficits and enhancements in NTAN1-deficient mice.
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The N-end rule is one ubiquitin-proteolytic pathway that relates the in vivo half-life of a protein to the identity of its N-terminal residue. NTAN1 deamidates N-terminal asparagine to aspartate, which is conjugated to arginine by ATE1. An N-terminal arginine-bearing substrate protein is recognized, ubiquitylated by UBR1/E3alpha, and subsequently degraded by 26S proteasomes. Previous research showed that NTAN1-deficient mice exhibited impaired long-term memory in the Lashley III maze. Therefore, a series of studies, designed to assess the role of NTAN1 in short- and intermediate-term memory processes, was undertaken. Two hundred sixty mice (126 -/-; 134 +/ +) received Lashley III maze training with intertrial intervals ranging from 2-180 min. Results indicated that inactivation of NTAN1 amidase differentially affects short-, intermediate-, and long-term memory. (+info)
Multiple central nervous system targets for eliciting beneficial effects on memory and cognition.
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The development of drugs for the treatment of disorders of cognition has benefited from a more precise knowledge of the loss of specific neural pathways associated with certain neurodegenerative diseases such as Alzheimer's disease (AD). The loss of basal forebrain cholinergic neurons in AD has engendered the development of new compounds that target various aspects of the cholinergic system. However, limitations in the effectiveness of the most common of these, the anticholinesterases, have fueled the race to provide more efficacious compounds. In an attempt to avoid side effects and improve efficacy, other neuronal targets have been considered, including receptors for norepinephrine, dopamine, serotonin, excitatory amino acids, neural peptides, and others. Our laboratory has had the opportunity to study the memory-enhancing potential of many of the compounds developed expressly for these neuronal targets in macaques. Upon reviewing 21 such studies it was evident that: 1) To varying degrees, pharmacological manipulation of each target yielded improved task performance. 2) Combining pharmacological targets could lead to additive or synergistic effects on task performance. 3) Mature adult and aged monkeys provided equivalent estimates of drug effectiveness. 4) There appeared to be no limiting level of task improvement for compounds tested in aged and younger monkeys. 5) Certain of these agents also exhibited potential disease-modifying actions. Thus, certain memory-enhancing agents may prove more useful when implemented early in the course of a disease such as AD, and they also may enjoy a wide application for the treatment of the memory decline associated with normal aging. (+info)
Protective effects of prenatal choline supplementation on seizure-induced memory impairment.
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Choline is an essential nutrient for rats and humans, and its availability during fetal development has long-lasting cognitive effects (Blusztajn, 1998). We investigated the effects of prenatal choline supplementation on memory deficits associated with status epilepticus. Pregnant rats received a control or choline-supplemented diet during days 11-17 of gestation. Male offspring [postnatal day 29 (P29)-32] were tested for their ability to find a platform in a water maze before and after administration of a convulsant dose of pilocarpine at P34. There were no differences between groups in water maze performance before the seizure. One week after status epilepticus (P41-P44), animals that had received the control diet prenatally had a drastically impaired performance in the water maze during the 4 d testing period, whereas prenatally choline-supplemented rats showed no impairment. Neither the seizures nor the prenatal availability of choline had any effect on hippocampal choline acetyltransferase or acetylcholinesterase activities. This study demonstrates that prenatal choline supplementation can protect rats against memory deficits induced by status epilepticus. (+info)
Lesions affecting the parahippocampal cortex yield spatial memory deficits in humans.
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Anatomical studies in monkeys, and functional imaging and lesion studies in humans, suggest that, within the primate medial temporal neocortex, the parahippocampal cortex (PHC) is particularly involved in spatial tasks. However, evidence for a functional specialization of the PHC regarding its spatial memory functions has so far been lacking. Here, we investigated spatial memory functions of the human perirhinal cortex (PRC) and PHC. Patients with lesions affecting the PRC but sparing the PHC, and patients with lesions affecting both PRC and PHC, performed an oculomotor delayed response task with unpredictably varied memory delays of up to 30 s. Compared to controls, patients with PRC+PHC lesions showed a significant delay-dependent inaccuracy of memory-guided eye movements contralateral to the lesion side, whereas patients with PRC lesions showed no significant inaccuracy. Our results show that the PHC is a critical component for spatial memory in humans and suggest that (i) extrahippocampal spatial memory functions of the medial temporal lobe may not be equally distributed in the medial temporal neocortex, but may be largely confined to the PHC, and (ii) damage to connections between cortices involved in spatial cognition and rostral regions of the temporal lobe is unlikely to account for the observed spatial memory deficits with PHC lesions. (+info)
[Nphe(1)]-Nociceptin (1-13)-NH(2), a nociceptin receptor antagonist, reverses nociceptin-induced spatial memory impairments in the Morris water maze task in rats.
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1. The present study was undertaken to investigate the effects of the novel nociceptin receptor antagonist, [Nphe(1)]-Nociceptin (1-13)-NH(2) (bilateral intrahippocampal injection, 50 nmole rat(-1)) on purported nociceptin-induced (bilateral intrahippocampal injection, 5 nmole rat(-1)) deficits in spatial learning in the rat Morris water maze task. In addition, experiments were performed in an 'open field' to investigate possible peptide-induced changes in exploratory behaviour. 2. Nociceptin significantly impaired the ability of the animal to locate the hidden platform throughout training (P<0.001 versus control group). 3. Pretreatment with [Nphe(1)]-Nociceptin (1-13)-NH(2) significantly blocked nociceptin-induced impairment of spatial learning (P<0.001 versus nociceptin group). 4. A probe trial revealed that vehicle-treated animals spent more time in the quadrant that had previously contained the hidden platform, whereas nociceptin-treated animals did not spend more time in any one quadrant. 5. Learning impairments were not attributable to non-specific deficits in motor performance or change in exploratory behaviour. 6. Taken together, our results reveal that [Nphe(1)]-Nociceptin (1-13)-NH(2) represents an effective and useful in vivo antagonist at the nociceptin receptors involved in learning and memory. (+info)