Synaptic Plasticity and Cognitive Ability in Experimental Adult-Onset Hypothyroidism.

Adult-onset hypothyroidism impairs normal brain function. Research on animal models of hypothyroidism has revealed critical information on how deficiency of thyroid hormones impacts the electrophysiological and molecular functions of the brain, which leads to the well known cognitive impairment in untreated hypothyroid patients. Currently, such information can only be obtained from experiments on animal models of hypothyroidism. This review summarizes important research findings that pertain to understanding the clinical cognitive consequences of hypothyroidism, which will provide a better guiding path for therapy of hypothyroidism. SIGNIFICANCE STATEMENT: Cognitive impairment occurs during adult-onset hypothyroidism in both humans and animal models. Findings from animal studies validate clinical findings showing impaired long-term potentiation, decreased CaMKII, and increased calcineurin. Such findings can only be gleaned from animal experiments to show how hypothyroidism produces clinical symptoms.

Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer's disease.

We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Aß1-42 peptide, 2weeks (250pmol/day). Aß infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Aß in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Aß proteins in both hippocampal areas. Exercise, however, did not affect the levels of these proteins in normal rats. We suggest that exercise might be changing the equilibrium of APP processing pathway towards the nonpathogenic pathway most probably via increasing BDNF levels in the brain of AD model.

Neuroprotective Effects of Nicotine on Hippocampal Long-Term Potentiation in Brain Disorders.

Long-term potentiation (LTP) is commonly considered the cellular correlate of learning and memory. In learning and memory impairments, LTP is invariably diminished in the hippocampus, the brain region responsible for memory formation. LTP is measured electrophysiologically in various areas of the hippocampus. Two mechanistically distinct phases of LTP have been identified: early phase LTP, related to short-term memory; and late-phase LTP, related to long-term memory. These two forms can be severely reduced in a variety of conditions but can be rescued by treatment with nicotine. This report reviews the literature on the beneficial effect of nicotine on LTP in conditions that compromise learning and memory.

Caffeine and REM sleep deprivation: Effect on basal levels of signaling molecules in area CA1.

We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treated with caffeine in drinking water (0.3g/l) for four weeks before they were REM sleep-deprived for 24h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylated- and total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation.

Caffeine treatment prevents rapid eye movement sleep deprivation-induced impairment of late-phase long-term potentiation in the dentate gyrus.

The CA1 and dentate gyrus (DG) are physically and functionally closely related areas of the hippocampus, but they differ in various respects, including their reactions to different insults. The purpose of this study was to determine the protective effects of chronic caffeine treatment on late-phase long-term potentiation (L-LTP) and its signalling cascade in the DG area of the hippocampus of rapid eye movement sleep-deprived rats. Rats were chronically treated with caffeine (300 mg/L drinking water) for 4 weeks, after which they were sleep-deprived for 24 h. L-LTP was induced in in anaesthetized rats, and extracellular field potentials from the DG area were recorded in vivo. The levels of L-LTP-related signalling proteins were assessed by western blot analysis. Sleep deprivation markedly reduced L-LTP magnitude, and basal levels of total cAMP response element-binding protein (CREB), phosphorylated CREB (P-CREB), and calcium/calmodulin kinase IV (CaMKIV). Chronic caffeine treatment prevented the reductions in the basal levels of P-CREB, total CREB and CaMKIV in sleep-deprived rats. Furthermore, caffeine prevented post-L-LTP sleep deprivation-induced downregulation of P-CREB and brain-derived neurotrophic factor in the DG. The current findings show that caffeine treatment prevents acute sleep deprivation-induced deficits in brain function.

Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer's disease.

Previously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aß1₋42 (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels of cognition-related signalling molecules. We showed that 4 wk of treadmill exercise totally prevented these impairments. Here, we evaluated the effect of exercise on non-cognitive function and basal synaptic transmission in the Cornu Ammonis 1 (CA1) area using the same AD model. Our results indicated that the anxiety behaviour of Aß-treated rats was prevented by 4 wk of treadmill exercise. Exercised/Aß-infused rats spent a longer time in the centre area of the open field (OF), elevated plus maze (EPM) paradigms and the light area of the light-dark (LD) box, which were similar to those of control and exercise rats. Furthermore, under basal conditions the aberrant up-regulation of calcineurin (PP2B) and reduction of phosphorylated Ca²âº/calmodulin dependent protein kinase II (p-CaMKII) levels induced by AD-like pathology were normalised by the exercise regimen. We conclude that regular exercise may exert beneficial effects on both cognitive and non-cognitive functions in this AD model.

Regular treadmill exercise prevents sleep deprivation-induced disruption of synaptic plasticity and associated signaling cascade in the dentate gyrus.

STUDY OBJECTIVES: Evidence suggests that regular exercise can protect against learning and memory impairment in the presence of insults such as sleep deprivation. The dentate gyrus (DG) area of the hippocampus is a key staging area for learning and memory processes and is particularly sensitive to sleep deprivation. The purpose of this study was to determine the effect of regular exercise on early-phase long-term potentiation (E-LTP) and its signaling cascade in the presence of sleep deprivation. EXPERIMENTAL DESIGN: Rats were exposed to 4 weeks of regular treadmill exercise then subsequently sleep-deprived for 24h using the modified multiple platform model before experimentation. We tested the effects of exercise and/or sleep deprivation using electrophysiological recording in the DG to measure synaptic plasticity; and Western blot analysis to quantify the levels of key signaling proteins related to E-LTP. MEASUREMENTS AND RESULTS: Regular exercise prevented the sleep deprivation-induced impairment of E-LTP in the DG area as well as the sleep deprivation-associated decrease in basal protein levels of phosphorylated and total α calcium/calmodulin-dependent protein kinase II (P/total-CaMKII) and brain-derived neurotrophic factor (BDNF). High frequency stimulation (HFS) to the DG area was used to model learning stimuli and increased the P-CaMKII and BDNF levels in normal animals: yet failed to change these levels in sleep-deprived rats. However, HFS in control and sleep-deprived rats increased the levels of the phosphatase calcineurin. In contrast, exercise increased BDNF and P-CaMKII levels in exercised/sleep-deprived rats. CONCLUSIONS: Regular exercise appears to exert a protective effect against sleep deprivation-induced spatial memory impairment by inducing hippocampal signaling cascades that positively modulate basal and stimulated levels of key effectors such as P-CaMKII and BDNF, while attenuating increases in the protein phosphatase calcineurin.

Role of α7- and α4ß2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory.

We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4ß2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4ß2-nAChRs [dihydro-ß-erythroidine (DHßE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 µg/side.d and 41 µg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHßE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4ß2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.

Grape powder supplementation prevents oxidative stress-induced anxiety-like behavior, memory impairment, and high blood pressure in rats.

We examined whether or not grape powder treatment ameliorates oxidative stress-induced anxiety-like behavior, memory impairment, and hypertension in rats. Oxidative stress in Sprague-Dawley rats was produced by using L-buthionine-(S,R)-sulfoximine (BSO). Four groups of rats were used: 1) control (C; injected with vehicle and provided with tap water), 2) grape powder-treated (GP; injected with vehicle and provided for 3 wk with 15 g/L grape powder dissolved in tap water), 3) BSO-treated [injected with BSO (300 mg/kg body weight), i.p. for 7 d and provided with tap water], and 4) BSO plus grape powder-treated (GP+BSO; injected with BSO and provided with grape powder-treated tap water). Anxiety-like behavior was significantly greater in BSO rats compared with C or GP rats (P < 0.05). Grape powder attenuated BSO-induced anxiety-like behavior in GP+BSO rats. BSO rats made significantly more errors in both short- and long-term memory tests compared with C or GP rats (P < 0.05), which was prevented in GP+BSO rats. Systolic and diastolic blood pressure was significantly greater in BSO rats compared with C or GP rats (P < 0.05), whereas grape powder prevented high blood pressure in GP+BSO rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK-1/2) was activated (P < 0.05), whereas levels of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) were significantly less (P < 0.05) in BSO but not in GP+BSO rats compared with C or GP rats. We suggest that by regulating brain ERK-1/2, GLO-1, GSR-1, CAMK-IV, CREB, and BDNF levels, grape powder prevents oxidative stress-induced anxiety, memory impairment, and hypertension in rats.

A high-salt diet further impairs age-associated declines in cognitive, behavioral, and cardiovascular functions in male Fischer brown Norway rats.

Aging-associated declines in cognitive, emotional, and cardiovascular function are well known. Environmental stress triggers critical changes in the brain, further compromising cardiovascular and behavioral health during aging. Excessive dietary salt intake is one such stressor. Here, we tested the effect of high salt (HS) on anxiety, learning-memory function, and blood pressure (BP) in male Fischer brown Norway (FBN) rats. Adult (A; 2 mo) and old (O; 20 mo) male rats were fed normal-salt (NS; 0.4% NaCl) or HS (8% NaCl) diets for 4 wk after being implanted with telemeter probes for conscious BP measurement. Thereafter, tests to assess anxiety-like behavior and learning-memory were conducted. The rats were then killed, and samples of plasma, urine, and brain tissue were collected. We found that systolic BP was higher in O-NS (117 ± 1.2 mm Hg) than in A-NS (105 ± 0.8 mm Hg) rats (P < 0.05). Furthermore, BP was higher in O-HS (124 ± 1.4 mm Hg) than in O-NS (117 ± 1.2 mm Hg) rats (P < 0.05). Moreover, anxiety-like behavior (light-dark and open-field tests) was not different between A-NS and O-NS rats but was greater in O-HS rats than in A-NS, O-NS, or A-HS rats (P < 0.05). Short-term memory (radial arm water maze test) was similar in A-NS and O-NS rats but was significantly impaired in O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05). Furthermore, oxidative stress variables (in plasma, urine, and brain) as well as corticosterone (plasma) were greater in O-HS rats when compared with A-NS, O-NS, or A-HS rats (P < 0.05). The antioxidant enzyme glyoxalase-1 expression was selectively reduced in the hippocampus and amygdala of O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05), whereas other antioxidant enzymes, glutathione reductase 1, manganese superoxide dismutase (SOD), and Cu/Zn SOD remained unchanged. We suggest that salt-sensitive hypertension and behavioral derangement are associated with a redox imbalance in the brain of aged FBN rats.

Neurobiological consequences of sleep deprivation.

Although the physiological function of sleep is not completely understood, it is well documented that it contributes significantly to the process of learning and memory. Ample evidence suggests that adequate sleep is essential for fostering connections among neuronal networks for memory consolidation in the hippocampus. Sleep deprivation studies are extremely valuable in understanding why we sleep and what are the consequences of sleep loss. Experimental sleep deprivation in animals allows us to gain insight into the mechanism of sleep at levels not possible to study in human subjects. Many useful approaches have been utilized to evaluate the effect of sleep loss on cognitive function, each with relative advantages and disadvantages. In this review we discuss sleep and the detrimental effects of sleep deprivation mostly in experimental animals. The negative effects of sleep deprivation on various aspects of brain function including learning and memory, synaptic plasticity and the state of cognition-related signaling molecules are discussed.

Thyroidectomy and PTU-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules.

BACKGROUND: The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. Hypothyroidism impairs hippocampus- dependent learning and memory in adult rats, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU) in terms of synaptic plasticity and the effect on underlying molecular mechanisms of spatial and non-spatial types of memory. METHODS: Hypothyroidism was induced using thyroidectomy or treatment with propylthiouracil (PTU). L-thyroxin was used as replacement therapy. Synaptic plasticity was evaluated using in vivo electrophysiological recording. Training in the radial arm water maze (RAWM), where rats had to locate a hidden platform, generated spatial and non-spatial learning and memory. Western blotting measured signaling molecules in the hippocampal area CA1 area. RESULTS: Our findings show that thyroidectomy and PTU models are equally effective, as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two models produced an identical degree of inhibition of synaptic plasticity as indicated by depression of long-term potentiation (LTP). For non-spatial memory, rats were trained to swim to a visible platform in an open swim field. Analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats, produced significant increases in the P-calcium calmodulin kinase II (P-CaMKII), protein kinase-C (PKCγ), calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats. CONCLUSION: Thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence.

Inadequate sleep is prevalent in modern societies and is known to profoundly impair cognitive function. We examined the impact of 4 weeks of regular treadmill exercise on sleep deprivation induced spatial learning and memory, synaptic plasticity and related signaling molecules in area CA1 of the rat hippocampus. Rats were exercised on a treadmill and subsequently sleep-deprived for 24h using the modified multiple platform technique. Testing of learning and short-term memory performance in the radial arm water maze showed that although sedentary sleep deprived rats were severely impaired, exercised sleep deprived rats' performance was normal. Extracellular recording from area CA1 of anesthetized rats revealed that early phase LTP (E-LTP) was markedly impaired in the sedentary sleep deprived animals, but was normal in the exercised sleep deprived group. Additionally, immunoblot analysis of CA1 area before (basal) and after expression of E-LTP indicated that the significant down-regulation of the brain derived neurotrophic factor (BDNF) and phosphorylated calcium-calmodulin dependent protein kinase II (P-CaMKII) levels in sleep deprived animals was prevented by the regular exercise regimen. The results suggest that the regular exercise protocol prevents the sleep deprivation induced impairments in short-term memory and E-LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CaMKII and BDNF associated with sleep deprivation.

Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia.

We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing.

Elevation of BACE in an Aß rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine.

In Alzheimer's disease (AD), progressive accumulation of ß-amyloid (Aß) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4ß2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aß production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4ß2-nAChR subunits using an Aß rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aß peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aß-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aß rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and ß2 were significantly decreased in Aß rats, but these were also normalized in Aß rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aß-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aß i.c.v.-infused rat as a model of AD.

Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF.

Chronic psychosocial stress enhances long-term depression in a subthreshold amyloid-beta rat model of Alzheimer's disease.

In addition to genetic aspects, environmental factors such as stress may also play a critical role in the etiology of the late onset, sporadic Alzheimer's disease (AD). The present study examined the effect of chronic psychosocial stress in a sub-threshold Aß (subAß) rat model of AD on long-term depression by two techniques: electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of memory- and AD-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAß rat model of AD, which was intended to represent outwardly normal individuals with a pre-disposition to AD, was induced by continuous infusion of 160 pmol/day Aß1₋42 via a 14-day i.c.v. osmotic pump. Results from electrophysiological recordings showed that long-term depression evoked in stress/subAß animals was significantly enhanced compared with that in animals exposed to stress or subAß infusion alone. Molecular analysis of various signaling molecules 1 h after induction of long-term depression revealed an increase in the levels of calcineurin and phosphorylated CaMKII in groups exposed to stress compared with other groups. The levels of the brain-derived neurotrophic factor (BDNF) were significantly decreased in stress/subAß animals but not in stress or subAß animals. In addition, the levels of beta-site amyloid precursor protein cleaving enzyme were markedly increased in stress/subAß. These findings suggest that chronic stress may accelerate the impairment of synaptic plasticity and consequently cognition in individuals 'at-risk' for AD.

Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer's disease.

Although it is generally agreed that Aß contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a subpathogenic dose of Aß; "subAß") rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning- and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAß rat model of AD was induced by continuous infusion of 160 pmol/day Aß(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subAß rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAß in chronically stressed rats (stress/subAß group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subAß rats, but not in the stress/subAß rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD.

Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction and deposition of beta-amyloid (Aß) in regions of the brain associated with learning and memory. The sporadic nature and late onset of most AD cases suggests that aside from biological determinants, environmental factors such as stress may also play a role in the progression of the disease. Behavioral and molecular studies were utilized to evaluate the effects of chronic nicotine treatment in the prevention of impairment of long-term memory. The rat model of AD was induced by i.c.v. osmotic pump infusion of Aß peptides. Chronic psychosocial stress and chronic nicotine treatment were instituted for 6weeks. Spatial memory testing in the Radial Arm Water Maze revealed that, although stress, by itself, did not affect long-term memory, the combination of chronic stress and Aß infusion impaired long-term memory significantly more than Aß peptides infusion alone. Chronic nicotine treatment completely prevented Aß- and stress/Aß combination-induced memory impairment. Furthermore, molecular findings in hippocampal CA1 region of stress/Aß rats indicated marked reduction in the protein levels of phosphorylated cAMP response element binding (p-CREB) and calcium-calmodulin-dependent protein kinase IV (CaMKIV), with significant increases in the levels of brain-derived neurotrophic factor (BDNF). These disturbances in signaling pathways, which may be the underlying mechanisms of impairment of long-term memory in these rats, were totally prevented by chronic nicotine treatment.

NMDA receptor-independent LTP in mammalian nervous system.

Long-term potentiation (LTP) of synaptic transmission is a form of activity-dependent synaptic plasticity that exists at most synapses in the nervous system. In the central nervous system (CNS), LTP has been recorded at numerous synapses and is a prime candidate mechanism associating activity-dependent plasticity with learning and memory. LTP involves long-lasting increase in synaptic strength with various underlying mechanisms. In the CNS, the predominant type of LTP is believed to be dependent on activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR), which is highly calcium-permeable. However, various forms of NMDAR-independent LTP have been identified in diverse areas of the nervous system. The NMDAR-independent LTP may require activation of glutamate metabotropic receptors (mGluR) or ionotropic receptors other than NMDAR such as nicotinic acetylcholine receptor (α7-nAChR), serotonin 5-HT3 receptor or calcium-permeable AMPA receptor (CP-AMPAR). In this review, NMDAR-independent LTP of various areas of the central and peripheral nervous systems are discussed.