Deficits In Hippocampal Synaptic Plasticity Research Articles

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1.

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.

Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor.

Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. Currently, there are an estimated 3.2-5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of 10 of these individuals report cognitive disabilities (Thurman et al., 1999; Lew et al., 2006; Zaloshnja et al., 2008). One of the molecular mechanisms associated with chronic cognitive disabilities is impaired cAMP signaling in the hippocampus. In this study, we report that a selective phosphodiesterase 4B (PDE4B) inhibitor reduces chronic cognitive deficits after TBI and rescues deficits in hippocampal long-term potentiation. These results suggest that PDE4B inhibition has the potential to improve learning and memory ability and overall functioning for people living with TBI.

Traumatic Brain Injury Upregulates Phosphodiesterase Expression in the Hippocampus.

Traumatic brain injury (TBI) results in significant impairments in hippocampal synaptic plasticity. A molecule critically involved in hippocampal synaptic plasticity, 3′,5′-cyclic adenosine monophosphate, is downregulated in the hippocampus after TBI, but the mechanism that underlies this decrease is unknown. To address this question, we determined whether phosphodiesterase (PDE) expression in the hippocampus is altered by TBI. Young adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. Animals were analyzed by western blotting for changes in PDE expression levels in the hippocampus. We found that PDE1A levels were significantly increased at 30 min, 1 h and 6 h after TBI. PDE4B2 and 4D2 were also significantly increased at 1, 6, and 24 h after TBI. Additionally, phosphorylation of PDE4A was significantly increased at 6 and 24 h after TBI. No significant changes were observed in levels of PDE1B, 1C, 3A, 8A, or 8B between 30 min to 7 days after TBI. To determine the spatial profile of these increases, we used immunohistochemistry and flow cytometry at 24 h after TBI. PDE1A and phospho-PDE4A localized to neuronal cell bodies. PDE4B2 was expressed in neuronal dendrites, microglia and infiltrating CD11b+ immune cells. PDE4D was predominantly found in microglia and infiltrating CD11b+ immune cells. To determine if inhibition of PDE4 would improve hippocampal synaptic plasticity deficits after TBI, we treated hippocampal slices with rolipram, a pan-PDE4 inhibitor. Rolipram partially rescued the depression in basal synaptic transmission and converted a decaying form of long-term potentiation (LTP) into long-lasting LTP. Overall, these results identify several possible PDE targets for reducing hippocampal synaptic plasticity deficits and improving cognitive function acutely after TBI.

Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity

Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD.

Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.

Vitamin C reverses lead-induced deficits in hippocampal synaptic plasticity in rats.

Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity.

Impact of combined prenatal ethanol and prenatal stress exposures on markers of activity-dependent synaptic plasticity in rat dentate gyrus

Prenatal ethanol exposure and prenatal stress can each cause long-lasting deficits in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms underlying these perturbations following a learning event are still poorly understood. We examined the effects of prenatal ethanol exposure and prenatal stress exposure, either alone or in combination, on the cytosolic expression of activity-regulated cytoskeletal (ARC) protein and the synaptosomal expression of AMPA-glutamate receptor subunits (GluA1 and GluA2) in dentate gyrus of female adult offspring under baseline conditions and after 2-trial trace conditioning (TTTC). Surprisingly, baseline cytoplasmic ARC expression was significantly elevated in both prenatal treatment groups. In contrast, synaptosomal GluA1 receptor subunit expression was decreased in both prenatal treatment groups. GluA2 subunit expression was elevated in the prenatal stress group. TTTC did not alter ARC levels compared to an unpaired behavioral control (UPC) group in any of the 4 prenatal treatment groups. In contrast, TTTC significantly elevated both synaptosomal GluA1 and GluA2 subunit expression relative to the UPC group in control offspring, an effect that was not observed in any of the other 3 prenatal treatment groups. Given ARC's role in regulating synaptosomal AMPA receptors, these results suggest that prenatal ethanol-induced or prenatal stress exposure-induced increases in baseline ARC levels could contribute to reductions in both baseline and activity-dependent changes in AMPA receptors in a manner that diminishes the role of AMPA receptors in dentate gyrus synaptic plasticity and hippocampal-sensitive learning.

Obesity Elicits Interleukin 1-Mediated Deficits in Hippocampal Synaptic Plasticity

Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1β (IL1β) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.

Omega-3 fatty acids can reverse the long-term deficits in hippocampal synaptic plasticity caused by prenatal ethanol exposure

Fetal alcohol spectrum disorders result in long-lasting neurological deficits including decreases in synaptic plasticity and deficits in learning and memory. In this study we examined the effects of prenatal ethanol exposure on hippocampal synaptic plasticity in male and female Sprague-Dawley rats. Furthermore, we looked at the capacity for postnatal dietary intervention to rescue deficits in synaptic plasticity. Animals were fed an omega-3 enriched diet from birth until adulthood (PND55–70) and in vivo electrophysiology was performed by stimulating the medial perforant path input to the dentate gyrus and recording field excitatory post-synaptic potentials. LTP was induced by administering bursts of five 400Hz pulses as a theta-patterned train of stimuli (200ms inter-burst interval). Ethanol-exposed adult males, but not females, exhibited a significant reduction in LTP. This deficit in male animals was completely reversed with an omega-3 enriched diet. These results demonstrate that omega-3 fatty acids can have benefits following prenatal neuropathological insults and may be a viable option for alleviating some of the neurological deficits associated with FASD.

Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

Irreversible N-methyl-D-aspartate receptor (NMDAR) antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP) of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments. The ability to express LTP at the perforant pathway – dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3, and 4 weeks after a single treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue. Taken together, these data support that acute treatment with an irreversible NMDAR-antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders.

Reversal of age‐related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting d‐serine‐dependent NMDA receptor activation

Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent D-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine-dependent pathway.

Astrocyte-Derived Adenosine and A1Receptor Activity Contribute to Sleep Loss-Induced Deficits in Hippocampal Synaptic Plasticity and Memory in Mice

Sleep deprivation (SD) can have a negative impact on cognitive function, but the mechanism(s) by which SD modulates memory remains unclear. We have previously shown that astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following a brief period of SD (Halassa et al., 2009). In this study, we examined whether genetic disruption of soluble N-ethylmaleimide-sensitive factor attached protein (SNARE)-dependent exocytosis in astrocytes (dnSNARE mice) or pharmacological blockade of A1 receptor signaling using an adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), could prevent the negative effects of 6 h of SD on hippocampal late-phase long-term potentiation (L-LTP) and hippocampus-dependent spatial object recognition memory. We found that SD impaired L-LTP in wild-type mice but not in dnSNARE mice. Similarly, this deficit in L-LTP resulting from SD was prevented by a chronic infusion of CPT. Consistent with these results, we found that hippocampus-dependent memory deficits produced by SD were rescued in dnSNARE mice and CPT-treated mice. These data provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of SD on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the hippocampus-related cognitive deficits induced by sleep loss.

Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus

Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese, and there is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). While the vast majority of these studies have focused on the hypothalamus, more recent studies suggest that the complications of obesity may also affect the structural and functional integrity of the hippocampus. A potential contributor to obesity-related CNS abnormalities is the adipocyte-derived hormone leptin. In this regard, decreases in CNS leptin activity may contribute to deficits in hippocampal synaptic plasticity and suggest that leptin resistance, a well-described phenomenon in the hypothalamus, may also be observed in the hippocampus. Unfortunately, the myriad of metabolic and endocrine abnormalities in diabetes/obesity phenotypes makes it challenging to assess the role of leptin in hippocampal neuroplasticity deficits associated with obesity models. To address this question, we examined hippocampal morphological and behavioral plasticity following lentivirus-mediated downregulation of hypothalamic insulin receptors (hypo-IRAS). Hypo-IRAS rats exhibit increases in body weight, adiposity, plasma leptin and triglyceride levels. As such, hypo-IRAS rats develop a phenotype that is consistent with features of the metabolic syndrome. In addition, hippocampal morphological plasticity and performance of hippocampal-dependent tasks are adversely affected in hypo-IRAS rats. Leptin-mediated signaling is also decreased in hypo-IRAS rats. We will discuss these findings in the context of how hyperleptinemia and hypertriglyceridemia may represent mechanistic mediators of the neurological consequences of impaired hippocampal synaptic plasticity in obesity.

Reversal of aging‐associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function

Deficits in learning and memory accompanied by age-related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in CA1 areas of hippocampal slices. Our results demonstrated that the impaired LTP induced by aging could be reversed by acute administration of reductants that can regulate thiol redox status directly, such as dithiothreitol or β-mercaptoethanol, but not by classical anti-oxidants such as vitamin C or trolox. This repair was mediated by the recruitment of aging-related deficits in NMDAR function induced by these reductants and was mimicked by glutathione, which can restore the age-associated alterations in endogenous thiol redox status. Moreover, antioxidant prevented but failed to reverse H(2)O(2) -induced impairment of NMDAR-mediated synaptic plasticity. These results indicate that the restoring of thiol redox status may be a more effective strategy than the scavenging of oxidants in the treatment of pre-existing oxidative injury in learning and memory.

Neurotrophins Enhance CaMKII Activity and Rescue Amyloid-β-Induced Deficits in Hippocampal Synaptic Plasticity

Amyloid-β (Aβ) peptide-induced impairment of hippocampal synaptic plasticity is considered an underlying mechanism for memory loss in the early stages of Alzheimer's disease and its animal models. We previously reported inhibition of long-term potentiation (LTP) and miniature excitatory postsynaptic currents by oligomeric Aβ(1-42) at hippocampal synapses. While multiple cellular mechanisms could be involved in Aβ-induced synaptic dysfunction, blockade of activity-dependent autophosphorylation of Ca2+ and calmodulin-dependent protein kinase II (CaMKII) appeared to be a major component of Aβ action in our studies. The present study further tested this hypothesis and examined the therapeutic potential of trkB receptor-acting neurotrophins in rescuing Aβ-induced synaptic and signaling impairments. As expected, treatment of rat hippocampal slices with Aβ(1-42) significantly reduced LTP in the Schaffer collateral-CA1 pathway and dentate medial perforant path. LTP-associated CaMKII activation and AMPA receptor phosphorylation were blocked by Aβ(1-42) at the same concentration that inhibited LTP. Aβ-induced LTP impairment, however, was prevented when slices were co-treated with neurotrophin 4 (NT4). Western blotting and immunohistochemical analyses confirmed that treatment with NT4 or brain-derived neurotrophic factor, another trkB-acting neurotrophin, could oppose Aβ action, enhancing autophosphorylation of CaMKII, and AMPA receptor phosphorylation at a CaMKII-dependent site. These findings support the view that CaMKII is a key synaptic target of Aβ toxicity as well as a potential therapeutic site of neurotrophins for Alzheimer's disease.

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

Prenatal ethanol exposure causes deficits in hippocampal synaptic plasticity and learning. At present, there are no clinically effective pharmacotherapeutic interventions for these deficits. In this study, we examined whether the cognition-enhancing agent 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl) benzonitrile (ABT-239), a histamine H(3) receptor antagonist, could ameliorate fetal ethanol-induced long-term potentiation (LTP) deficits. Long-Evans rat dams consumed a mean of 2.82 g/kg ethanol during a 4-h period each day. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, offspring litter size, and birth weights were not different between ethanol-consuming and control groups. A stimulating electrode was implanted in the entorhinal cortical perforant path, and a recording electrode was implanted in the dorsal dentate gyrus of urethane-anesthetized adult male offspring. Baseline input/output responses were not affected either by prenatal ethanol exposure or by 1 mg/kg ABT-239 administered 2 h before data collection. No differences were observed between prenatal treatment groups when a 10-tetanus train protocol was used to elicit LTP. However, LTP elicited by 3 tetanizing trains was markedly impaired by prenatal ethanol exposure compared with control. This fetal ethanol-induced LTP deficit was reversed by ABT-239. In contrast, ABT-239 did not enhance LTP in control offspring using the 3-tetanus train protocol. These results suggest that histamine H(3) receptor antagonists may have utility for treating fetal ethanol-associated synaptic plasticity and learning deficits. Furthermore, the differential effect of ABT-239 in fetal alcohol offspring compared with controls raises questions about the impact of fetal ethanol exposure on histaminergic modulation of excitatory neurotransmission in affected offspring.

Neural Cell Adhesion Molecule-Associated Polysialic Acid Regulates Synaptic Plasticity and Learning by Restraining the Signaling through GluN2B-Containing NMDA Receptors

The neural cell adhesion molecule (NCAM) is the predominant carrier of alpha2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca(2+) transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

Insulin signaling effects on memory and mood

The escalating obesity/diabetes epidemic is an important health-care issue that has crucial socio-economic ramifications. The complications of diabetes/obesity phenotypes extend to the central nervous system (CNS), including the hippocampus, a brain region that is particularly vulnerable to hyperglycemia and insulin resistance. Deficits in hippocampal synaptic plasticity observed in diabetes ultimately have deleterious consequences upon cognitive function. For example, recent studies using brain imaging technologies have identified cerebral atrophy in diabetic patients, suggesting that the neuroanatomical changes observed in experimental models of diabetes may accurately reflect what is occurring in the clinical setting. Deficits in insulin receptor (IR) signaling and impairments in hypothalamic-pituitary-adrenal (HPA) axis function also contribute to the neurological complications of diabetes phenotypes. The pathophysiological similarities between diabetes and stress-related mood disorders suggest that common mechanistic mediators may be involved in the etiology and progression of the neurological complications of these disorders. When combined with the accumulating evidence from pre-clinical models, these data support the hypothesis that a long-term consequence of diabetes/obesity phenotypes is accelerated brain aging that results in neuropsychological deficits and increased vulnerability to co-morbidities such as depressive illness.

Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats

Exposure to environmentally relevant levels of lead (Pb 2+) during early life produces deficits in hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and spatial learning in young adult rats [Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233–242; Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 53:50–56]. Other evidence suggests that the performance of rats in the Morris water maze spatial learning tasks is associated with the level of granule cell neurogenesis in the dentate gyrus (DG) [ Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza P-V, Abrous DN (2003) Spatial memory performance of aged rats in the water maze predicts level of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100:14385–14390]. In this study, we examined whether continuous exposure to environmentally relevant levels of Pb 2+ during early life altered granule cell neurogenesis and morphology in the rat hippocampus. Control and Pb 2+-exposed rats received bromodeoxyuridine (BrdU) injections (100 mg/kg; i.p.) for five consecutive days starting at postnatal day 45 and were killed either 1 day or 4 weeks after the last injection. The total number of newborn cells in the DG of Pb 2+-exposed rats was significantly decreased (13%; P<0.001) 1 day after BrdU injections relative to controls. Further, the survival of newborn cells in Pb 2+-exposed rats was significantly decreased by 22.7% ( P<0.001) relative to control animals. Co-localization of BrdU with neuronal or astrocytic markers did not reveal a significant effect of Pb 2+ exposure on cellular fate. In Pb 2+-exposed rats, immature granule cells immunolabeled with doublecortin (DCX) displayed aberrant dendritic morphology. That is, the overall length-density of the DCX-positive apical dendrites in the outer portion of the DG molecular layer was significantly reduced up to 36% in the suprapyramidal blade only. We also found that the area of Timm’s-positive staining representative of the mossy fibers terminal fields in the CA3 stratum oriens (SO) was reduced by 26% in Pb 2+-exposed rats. These findings demonstrate that exposure to environmentally relevant levels of Pb 2+ during early life alters granule cell neurogenesis and morphology in the rat hippocampus. They provide a cellular and morphological basis for the deficits in synaptic plasticity and spatial learning documented in Pb 2+-exposed animals.

Preserved synaptic vesicle recycling in hippocampal neurons in a mouse Alzheimer’s disease model

A recently described triple-transgenic mouse model (3×Tg, PS1 M146V, APP Swe, and tau P301L) develops a neuropathology similar to the brains of Alzheimer’s disease patients including progressive deposits of plaques and tangles [Neuron 39 (2003) 409]. These mice also show age-related deficits in hippocampal synaptic plasticity that occurs before the development of plaques and tangles. Here we report unchanged synaptic vesicle recycling, as measured by FM1-43 release, in the hippocampal neurons of the 3×Tg mice. Expression levels of presynaptic protein synaptophysin and of proteins involved in synaptic vesicle recycling including AP180, dynamin I, and synaptotagmin I also remain unaffected. These data suggest that the synaptic deficits observed in the 3×Tg neurons may not arise from the preserved synaptic vesicle recycling.