Smoking Progression and Nicotine-Enhanced Reward Sensitivity Predicted by Resting-State Functional Connectivity in Salience and Executive Control Networks.

INTRODUCTION: The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC) during smoking abstinence predicts nicotine-enhanced reward sensitivity and smoking progression in young light smokers. We hypothesized that high rsFC between brain areas with high densities of nicotinic receptors (insula, anterior cingulate cortex [ACC], hippocampus, thalamus) and areas involved in reward-seeking (nucleus accumbens [NAcc], prefrontal cortex [PFC]) would predict nicotine-enhanced reward sensitivity and smoking progression. METHODS: Young light smokers (N=64, age 18-24, M = 1.89 cigarettes/day) participated in the study. These individuals smoked between 5 to 35 cigarettes per week and lifetime use never exceeded 35 cigarettes per week. Their rsFC was assessed using functional magnetic resonance imaging after 14-hour nicotine-deprivation. Subjects also completed a probabilistic reward task after smoking a placebo on one day and a regular cigarette on another day. RESULTS: The probabilistic-reward-task assessed greater nicotine-enhanced reward sensitivity was associated with greater rsFC between the right anterior PFC and right NAcc, but with reduced rsFC between the ACC and left inferior prefrontal gyrus and the insula and ACC. Decreased rsFC within the salience network (ACC and insula) predicted increased smoking progression across 18 months and greater nicotine-enhanced reward sensitivity. CONCLUSIONS: These findings provide the first evidence that differences in rsFCs in young light smokers are associated with nicotine-enhanced reward sensitivity and smoking progression. IMPLICATIONS: Weaker rsFC within the salience network predicted greater nicotine-enhanced reward sensitivity and smoking progression. These findings suggest that salience network rsFC and drug-enhanced reward sensitivity may be useful tools and potential endophenotypes for reward sensitivity and drug-dependence research.

Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aß.

Deposition of ß -amyloid (Aß) peptides, cleavage products of ß-amyloid precursor protein (APP) by ß-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aß approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aß peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aß efficacy. The present study compared active γ-secretase binding sites with Aß deposition in aged and AD human cerebrum, and explored the possibility of Aß production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and ß-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aß40 and Aß42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aß, probably at reduced levels in AD.

Symbol relations training improves cognitive functioning in students with neurodevelopmental disorders.

Students with neurodevelopmental disorders [Specific Learning Disorders (SLD), Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD)] often experience learning challenges due to underlying weaknesses in cognitive processes. As these are some of the most common conditions to impact functioning, the development of effective treatments is a priority for neuropsychologists. However, the task of designing effective cognitive interventions has proven one of the most difficult challenges for our field. The Arrowsmith Program uses a novel approach compared to other cognitive intervention programs. We hypothesized that intensive practice of one aspect of this program would lead to improved cognitive functions in students with neurodevelopmental disorders. Twenty-seven students with neurodevelopmental disorders (ages 9.4-18.4 years) were recruited from Arrowsmith schools. Cognitive baseline and post-intervention data were gathered using components of the Woodcock-Johnson IV Tests of Cognitive Abilities. The intervention consisted of 6 weeks of intensive practice of the Symbol Relations Task. W-scores were used in a paired sample t-test analysis to determine if cognitive skill improvement occurred. Significant improvements were found in several measures of neuropsychological assessment, in particular in the Cattell-Horn-Carroll broad abilities These results provide a foundation for further work examining the utility of this novel approach to cognitive intervention.

APOE genotype influences P3b amplitude and response to smoking abstinence in young adults.

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice.

Deleterious mutations within the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. While whole animal deletion of Deaf1 in mice is lethal, mice with conditional disruption of the gene in neuronal precursor cells can display memory deficits and increased anxiety-like behavior. This study aimed to further characterize learning and memory alterations and assess changes in marble burying activity and hippocampal size in mice with conditional deletion of Deaf1. Mice lacking DEAF1 in the CNS (NKO) displayed reduced memory in both contextual fear conditioning and a 3-day massed trials Morris water maze paradigm. NKO mice had reduced marble burying activity in full cage marble burying tests. Using a half-cage marble test, NKO mice again buried fewer marbles and spent significantly more time on the side of the cage away from the marbles compared to control animals. The area of the dorsal hippocampus of NKO mice was decreased compared to control and animals with a single Deaf1 allele. These results continue to establish the importance of DEAF1 in cognitive behavior and provide new evidence that DEAF1 regulates hippocampal morphology.

Butein attenuates the cytotoxic effects of LPS-stimulated microglia on the SH-SY5Y neuronal cell line.

Neuroinflammation is involved in brain aging and neuronal cell death in neurodegenerative diseases such as Alzheimer's disease (AD). Butein has been suggested to have anti-inflammatory, anti-apoptotic, and anti-cancer effects. However, few studies have been done to evaluate whether butein exerts protective effects on neurons, and the potential mechanism for this effect has not been studied. Here, we examined the effect of butein on SH-SY5Y neuroblastoma cells grown with conditioned medium from BV2 microglia cells that had been activated by lipopolysaccharide (LPS) as a neuroinflammation model. We found butein pretreatment significantly increased SH-SY5Y cell viability in a dose-dependent manner by inhibiting the apoptosis normally induced by microglia-conditioned medium. SH-SY5Y cells treated with microglia-conditioned medium showed upregulated ERK signaling pathway-related mRNA expression and protein phosphorylation, which was dose-dependently reversed by butein. Immunocytochemistry and Western blot results showed that BV2-LPS conditioned medium-induced Nuclear factor kappaB (NF-κB) transactivational activity in SH-SY5Y cells, but this was attenuated by butein treatment of the BV2 cells prior to their exposure to LPS. Collectively, our results indicate that butein effectively mitigates inflammatory injury caused by LPS-conditioned medium from microglia, possibly due to reductions in the transactivational activity of NF-κB p65 and ERK signaling pathway activation, and provide evidence for a neuroprotective role of butein through blocking negative consequences of microglial activation.

Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-ß plaques; Aß) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats.

Although expression of some genes is known to change during neuronal activity or plasticity, the overall relationship of gene expression changes to memory or memory disorders is not well understood. Here, we combined extensive statistical microarray analyses with behavioral testing to comprehensively identify genes and pathways associated with aging and cognitive dysfunction. Aged rats were separated into cognitively unimpaired (AU) or impaired (AI) groups based on their Morris water maze performance relative to young-adult (Y) animals. Hippocampal gene expression was assessed in Y, AU, and AI on the fifth (last) day of maze training (5T) or 21 d posttraining (21PT) and in nontrained animals (eight groups total, one array per animal; n = 78 arrays). ANOVA and linear contrasts identified genes that differed from Y generally with aging (differed in both AU and AI) or selectively, with cognitive status (differed only in AI or AU). Altered pathways/processes were identified by overrepresentation analyses of changed genes. With general aging, there was downregulation of axonal growth, cytoskeletal assembly/transport, signaling, and lipogenic/uptake pathways, concomitant with upregulation in immune/inflammatory, lysosomal, lipid/protein degradation, cholesterol transport, transforming growth factor, and cAMP signaling pathways, primarily independent of training condition. Selectively, in AI, there was downregulation at 5T of immediate-early gene, Wnt (wingless integration site), insulin, and G-protein signaling, lipogenesis, and glucose utilization pathways, whereas Notch2 (oligodendrocyte development) and myelination pathways were upregulated, particularly at 21PT. In AU, receptor/signal transduction genes were upregulated, perhaps as compensatory responses. Immunohistochemistry confirmed and extended selected microarray results. Together, the findings suggest a new model, in which deficient neuroenergetics leads to downregulated neuronal signaling and increased glial activation, resulting in aging-related cognitive dysfunction.

Evidence for altered insulin receptor signaling in Alzheimer's disease.

Epidemiological data have shown that metabolic disease can increase the propensity for developing cognitive decline and dementia, particularly Alzheimer's disease (AD). While this interaction is not completely understood, clinical studies suggest that both hyper- and hypoinsulinemia are associated with an increased risk for developing AD. Indeed, insulin signaling is altered in post-mortem brain tissue from AD patients and treatments known to enhance insulin signaling can improve cognitive function. Further, clinical evidence has shown that AD patients and mouse models of AD often display alterations in peripheral metabolism. Since insulin is primarily derived from the periphery, it is likely that changes in peripheral insulin levels lead to alterations in central nervous system (CNS) insulin signaling and could contribute to cognitive decline and pathogenesis. Developing a better understanding of the relationship between alterations in peripheral metabolism and cognitive function might provide a foundation for the development of better treatment options for patients with AD. In this article we will begin to piece together the present data defining this relationship by briefly discussing insulin signaling in the periphery and CNS, its role in cognitive function, insulin's relationship to AD, peripheral metabolic alterations in mouse models of AD and how information from these models helps understand the mechanisms through which these changes potentially lead to impairments in insulin signaling in the CNS, and potential ways to target insulin signaling that could improve cognitive function in AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aß) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD-related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre-diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre-diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre-diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD-related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4-6 and 8-9months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild-type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2months of age, while extracellular Aß1-42 deposition occurs later and cognitive decline exists at 8-9months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild-type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre-diabetic phenotype prior to the development of AD-like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.

Experimentally induced diabetes worsens neuropathology, but not learning and memory, in middle aged 3xTg mice.

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The cause of the disease is still unknown, but amyloid plaques and neurofibrillary tangles in the brain are thought to play a role. However, transgenic mouse models expressing these neuropathological features do not show severe or consistent cognitive impairments. There is accumulating evidence that diabetes increases the risk for developing AD. We tested the hypothesis that experimentally induced diabetes would exacerbate cognitive symptoms in a mouse model of AD. Diabetes was induced in 12-month old 3xTg mice using streptozotocin (STZ; 90mg/kg, i.p., on two successive days). Hyperglycemia was verified by sampling blood glucose levels. Three months after injection (at 15 months of age), the mice were behaviorally tested in the Morris water maze and contextual fear conditioning. Subsequently, the hippocampal region was examined using immunohistochemistry (6E10 antibody for amyloid) and immunoblotting (AT8 antibody for phosphorylated tau). No differences were found in learning or memory between the vehicle-treated control and STZ-treated groups. A significant increase in the number of amyloid-positive plaques was observed in the subiculum of STZ-treated mice; very few plaques were seen in other hippocampal regions in either group. No differences in AT8 load were observed. These results reinforce that amyloid plaques, per se, are not sufficient to cause memory impairments. Further, while diabetes can enhance this aspect of brain pathology, the combination of disrupted glucose metabolism and the transgenes is still not sufficient to cause the severe cognitive impairments associated with clinical AD.

The slow afterhyperpolarization in hippocampal CA1 neurons covaries with spatial learning ability in aged Fisher 344 rats.

Rodents commonly exhibit age-related impairments in spatial learning tasks, deficits widely thought to reflect cellular or synaptic dysfunction in the hippocampus. Using whole-cell recordings, we examined the afterhyperpolarization (AHP) in CA1 pyramidal cells in hippocampal slices from young (4-6 months of age) and aged (24-26 months of age) Fisher 344 male rats that had been behaviorally characterized in the Morris water maze. The slow AHP (sAHP) recorded from learning-impaired aged rats (AI) was significantly larger than that seen in either age-matched unimpaired rats or young controls. Among aged rats, sAHP amplitude was inversely correlated with both acquisition and probe performance in the water maze. Action potential parameters among the three groups were similar, except for spike accommodation, which was more pronounced in the AI group. Intracellular application of the cAMP analog 8-CPT-cAMP suppressed the sAHP but failed to reveal any age- or performance-related differences in the medium AHP. 8-CPT-cAMP abolished the age-related difference in spike accommodation, whereas instantaneous firing frequency was unchanged. Calcium spikes were of similar amplitude in all three groups but were broader and had significantly larger tails in aged rats; these age-related changes could be mimicked in young neurons after exposure to BayK8644. The calcium spike among aged rats correlated with task acquisition in the maze but, unlike the sAHP, failed to correlate with probe performance. This is the first demonstration that sAHP amplitude covaries with spatial learning ability in aged rats, implying that CA1 excitability strongly influences certain aspects of cognitive function. Our findings also indicate that multiple processes, in addition to elevated calcium influx, conspire to induce cognitive decline during aging.

Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats.

RATIONALE: Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained. OBJECTIVE: Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior. MATERIALS AND METHODS: Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out. RESULTS: In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant-like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [(3)H]rolipram and [(3)H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram. CONCLUSION: These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior.

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.

RATIONALE: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. OBJECTIVES: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. MATERIALS AND METHODS: The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. RESULTS: Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). CONCLUSIONS: These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Soluble Abeta and cognitive function in aged F-344 rats and Tg2576 mice.

Recent findings suggest that Alzheimer's dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine. On the other hand, in aged Tg2576+ mice, cognitive deficits were related to levels of soluble Abeta, not insoluble Abeta, despite the fact that the levels of insoluble Abeta were thousands of times higher than the levels of soluble Abeta. The results of the present experiments suggest that vulnerability to cognitive deficits after scopolamine challenge is not related to elevated levels of soluble Abeta, but that high levels of soluble Abeta are more closely correlated with cognitive deficits than the amount insoluble Abeta, even after large amounts of aggregated, insoluble Abeta have been deposited.

The essential role of hippocampal alpha6 subunit-containing GABAA receptors in maternal separation stress-induced adolescent depressive behaviors.

Exposure to early stressful adverse life events such as maternal separation severely impacts the development of the nervous system. Using immunohistochemistry, quantitative PCR and Western blot approaches, we found that alpha6 subunit-containing GABAA receptors (Gabra6-containing GABAA Rs) were expressed on hippocampal interneurons of adolescent rats. Maternal separation stress (MS) from postnatal day 2 to15 significantly reduced Gabra6 expression and provoked depressive behaviors such as anhedonia. Furosemide, the selective antagonist of Gabra6-containing GABAARs, strongly increased peak amplitude of evoked IPSCs at CA3-CA1 synapses and the frequency of miniature IPSPs recorded from CA1 pyramidal cells in naive control animals, and this effect was occluded in MS animals. Knockdown of Gabra6 expression in hippocampus mimicked furosemide's effect and was sufficient to produce similar depressive symptoms that were observed in MS animals. These results indicate that the Gabra6-containing GABAA R is a key modulator of hippocampal synaptic transmission and likely plays a crucial role in the pathophysiology of maternal separation-induced depression.

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation.

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.

Theta-frequency synaptic potentiation in CA1 in vitro distinguishes cognitively impaired from unimpaired aged Fischer 344 rats.

Hippocampal-dependent learning and memory deficits have been well documented in aging rodents. The results of several recent studies have suggested that these deficits arise from weakened synaptic plasticity within the hippocampus. In the present study, we examined the relationship between hippocampal long-term potentiation (LTP) in vitro and spatial learning in aged (24-26 months) Fischer 344 rats. We found that LTP induced in the CA1 region using theta-frequency stimulation (5 Hz) is selectively impaired in slices from a subpopulation of aged rats that had shown poor spatial learning in the Morris water maze. LTP at 5 Hz in aged rats that did not show learning deficits was similar to that seen in young (4-6 months) controls. We also found that 5 Hz LTP amplitude strongly correlated with individual learning performance among aged rats. The difference in 5 Hz LTP magnitude among aged rats was not attributable to an altered response to 5 Hz stimulation or to differences in the NMDA receptor-mediated field EPSP. In addition, no performance-related differences in LTP were seen when LTP was induced with 30 or 70 Hz stimulation protocols. Finally, both 5 Hz LTP and spatial learning in learning-impaired rats were enhanced with the selective muscarinic M2 antagonist BIBN-99 (5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one). These findings reinforce the idea that distinct types of hippocampal LTP offer mechanistic insight into age-associated cognitive decline.

Phosphodiesterase inhibitors for cognitive enhancement.

An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.