Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice

In the present study, we used high-speed chronoamperometry to examine serotonin (5-HT) transporter (5-HTT) function in vivo in 2-, 5-, and 10-month-old brain-derived neurotrophic factor (BDNF)+/- mice. The rate of clearance of exogenously applied 5-HT was measured in CA3 region of hippocampus. In 2-month-old mice, the rate of 5-HT clearance did not differ between BDNF+/+ and BDNF+/- mice. In BDNF+/+ mice, 5-HT clearance rate (Tc) increased markedly with age. In contrast, Tc remained relatively static in BDNF+/- mice across 2-, 5-, and 10-month age groups. At 5 months of age, female BDNF+/+ mice had a lower maximal velocity (Vmax) for 5-HT clearance than male BDNF+/+ mice. There was a similar trend in 5-month-old BDNF+/- mice, but this did not reach statistical significance. There was an age-dependent increase in KT value for 5-HT clearance (i.e., decreased in vivo affinity of 5-HTT), but no significant effect of genotype or gender. 5-HTT density, as measured by [3H]cyanoimipramine binding, was not different between BDNF+/+ and BDNF+/- mice, although there was a significant increase in 5-HTT binding with age. The selective 5-HT reuptake inhibitor fluvoxamine (50 and 100 pmol) significantly decreased 5-HT clearance in BDNF+/+ mice, but not in BDNF+/- mice. Our data suggest that the profoundly reduced ability of 5- and 10-month-old BDNF+/- mice to clear 5-HT is not because of a decrease in the total number of 5-HTTs, but may be due to functional deficits in the 5-HTT, e.g., in the machinery/signaling required for insertion of 5-HTTs into the plasma membrane and/or activation of the 5-HTT once it is positioned to take up 5-HT from extracellular fluid.     

P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice

Memory impairment is the most common symptom in patients with Alzheimer’s disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition-enhancing potential.     

Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice

Heterozygous brain-derived neurotrophic factor (BDNF) (+/-) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/-) mice alcohol drinking behavior, as well as central 5-hydroxytryptamine (5-HT)1A receptor function at the level of 5-HT1A receptor-G protein interaction. BDNF (+/-) mice displayed increased ethanol intake in a two-bottle choice procedure. There was no difference in the preference ratio for non-alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol-naive mice, we measured [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-dipropyl-aminotetralin hydrobromide (8-OH-DPAT; 1 microM). In BDNF (+/-) versus wild-type (WT) mice, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/-)8-OH-DPAT-stimulated [35S]GTP gamma S binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in BDNF (+/-) mice. 5-HT1A receptor-stimulated [35S]GTP gamma S binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5-HT1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5-HT1A receptor function, specifically the capacity of the 5-HT1A receptor to activate G proteins, is attenuated in BDNF (+/-) mice.     

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

Spinal cord injury (SCI), a severe health problem in worldwide, was commonly associated with functional disability and reduced quality of life. As the expression of brain-derived neurotrophic factor (BDNF) was substantial event in injured spinal cord, we hypothesized whether BDNF-overexpression could be in favor of the recovery of both sensory function and hindlimb function after SCI. By using BDNF-overexpression transgene mice [CMV-BDNF 26 (CB26) mice] we assessed the role of BDNF on the recovery of neurological behavior in spinal cord transection (SCT) model. BMS score and tail-flick test was performed to evaluate locomotor function and sensory function, respectively. Immunohistochemistry was employed to detect the location and the expression of BDNF, NeuN, 5-HT, GAP-43, GFAP as well as CGRP, and the level of p-AKT and AKT were examined through western blot analysis. BDNF overexpressing resulted in significant locomotor functional recovery from 21 to 28 days after SCT, compared with wild type (WT)+SCT group. Meanwhile, the NeuN, 5-HT and GAP-43 positive cells were markedly increased in ventral horn in BDNF overexpression animals, compared with WT mice with SCT. Moreover, the crucial molecular signal, p-AKT/AKT has been largely up-regulated, which is consistent with the improvement of locomotor function. However, in this study, thermal hyperpathia encountered in sham (CB26) group and WT+SCT mice and further aggravated in CB26 mice after SCT. Also, following SCT, the significant augment of positive-GFAP astrocytes and CGRP fibers were found in WT+SCT mice, and further increase was seen in BDNF over-expression transgene mice. BDNF-overexpression may not only facilitate the recovery of locomotor function via AKT pathway, but also contributed simultaneously to thermal hyperalgesia after SCT.     

Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats

Cerebrolysin (CBL), a mixture of several active peptide fragments and neurotrophic factors including brain-derived neurotrophic factor (BDNF), is currently used in the management of cognitive alterations in patients with dementia. Since Cognitive decline as well as increased dementia are strongly associated with diabetes and previous studies addressed the protective effect of BDNF in metabolic syndrome and type 2 diabetes; hence this work aimed to evaluate the potential neuroprotective effect of CBL in modulating the complications of hyperglycaemia experimentally induced by streptozotocin (STZ) on the rat brain hippocampus. To this end, male adult Sprague Dawley rats were divided into (i) vehicle- (ii) CBL- and (iii) STZ diabetic-control as well as (iv) STZ+CBL groups. Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c%), which were associated by weight loss, elevated tumor necrosis factor (TNF)-α and decreased insulin growth factor (IGF)-1β in the serum. Uncontrolled hyperglycemia caused learning and memory impairments that corroborated degenerative changes, neuronal loss and expression of caspase (Casp)-3 in the hippocampal area of STZ-diabetic rats. Behavioral deficits were associated by decreased hippocampal glutamate (GLU), glycine, serotonin (5-HT) and dopamine. Moreover, diabetic rats showed an increase in hippocampal nitric oxide and thiobarbituric acid reactive substances versus decreased non-protein sulfhydryls. Though CBL did not affect STZ-induced hyperglycemia, it partly improved body weight as well as HbA1c%. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas and reduced Casp-3 expression. CBL improved serum TNF-α and IGF-1β, GLU and 5-HT as well as hampering oxidative biomarkers. In conclusion, CBL possesses neuroprotection against diabetes-associated cerebral neurodegeneration and cognitive decline via anti-inflammatory, antioxidant and antiapototic effects.     

NMDA receptor dysfunction contributes to impaired brain‐derived neurotrophic factor‐induced facilitation of hippocampal synaptic transmission in a Tau transgenic model

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain‐derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus‐dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor‐dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N‐methyl‐d‐Aspartate receptors (NMDAR). Using THY‐Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA‐induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY‐Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.     

Effects of Treadmill Exercise on Motor and Cognitive Function Recovery of MCAO Mice Through the Caveolin-1/VEGF Signaling Pathway in Ischemic Penumbra

Exercise has been regarded as an effective rehabilitation strategy to facilitate motor and cognitive functional recovery after stroke, even though the complex effects associated with exercise-induced repair of cerebral ischemic injury are not fully elucidated. The enhancement of angiogenesis and neurogenesis, and the improvement of synaptic plasticity following moderate exercise are conducive to functional recovery after ischemic damage. Our previous studies have confirmed the angiogenesis and neurogenesis through the caveolin-1/VEGF pathway in MCAO rats. As an essential neurotrophic factor, BDNF has multiple effects on ischemic injury. In this study, we attempted to determine an additional mechanism of treadmill exercise-mediated motor and cognitive functional recovery through the caveolin-1/VEGF pathway associated with BDNF in the ischemic penumbra of MCAO mice. We found that mice exposed to treadmill exercise after the MCAO operation showed a significant up-regulation in expression of caveolin-1, VEGF, BDNF, synapsin I and CYFIP1 proteins, numbers of cells positive for BrdU/CD34, BDNF, BrdU/NeuN, BrdU/Synapsin I and CYFIP1 expression were increased, which support the reduction in neurological deficit and infarction volume, as well as improved synaptic morphology and spatial learning abilities, compared with the non-exercise mice. However, the caveolin-1 inhibitor, daidzein, resulted in increase in neurological deficit and infarction volume. The selective VEGFR2 inhibitor, PD173074, significantly induced larger infarction volume and neurological injury, and decreased the expression of BDNF in the ischemic penumbra. These findings indicate that exercise improves angiogenesis, neurogenesis and synaptic plasticity to ameliorate motor and cognitive impairment after stroke partially through the caveolin-1/VEGF pathway, which is associated with the coregulator factor, BDNF.

     

Epigallocatechin-3-Gallate Ameliorated Iron Accumulation and Apoptosis and Promoted Neuronal Regeneration and Memory/Cognitive Functions in the Hippocampus Induced by Exposure to a Chronic High-Altitude Hypoxia Environment

We aimed to explore the protective effects and potential treatment mechanism of Epigallocatechin-3-gallate (EGCG) in an animal model of chronic exposure in a natural high-altitude hypoxia (HAH) environment. Behavioral alterations were assessed with the Morris water maze test. Iron accumulation in the hippocampus was detected by using DAB enhanced Perls’ staining, MRI, qPCR and colorimetry, respectively. Oxidative stress (malondialdehyde, MDA), apoptosis (Caspase-3), and neural regeneration (brain-derived neurotrophic factor, BDNF) were detected by using ELISA and western blotting. Neural ultrastructural changes were evaluated by transmission electron microscopy (TEM). The results showed that learning and memory performance of rats decreased when exposure to HAH environment. It was followed by iron accumulation, dysfunctional iron metabolism, reduced BDNF and the upregulation of MDA and Caspase-3. TEM confirmed the ultrastructural changes in neurons and mitochondria. EGCG reduced HAH-induced cognitive impairment, iron deposition, oxidative stress, and apoptosis and promoted neuronal regeneration against chronic HAH-mediated neural injury.

     

Strength exercise suppresses STZ-induced spatial memory impairment and modulates BDNF/ERK-CAMKII/CREB signalling pathway in the hippocampus of mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has generated scientific interest because of its prevalence in the population. Studies indicate that physical exercise promotes neuroplasticity and improves cognitive function in animal models and in human beings. The aim of the present study was to investigate the effects of strength exercise on the hippocampal protein contents and memory performance in mice subjected to a model of sporadic AD induced by streptozotocin (STZ). Swiss mice received two injections of STZ (3 mg/kg, intracerebroventricular). After 21 days, they began physical training using a ladde. Mice performed this protocol for 4 weeks. After the last exercise training session, mice performed the Morris Water Maze test. The samples of hippocampus were excised and used to determine protein contents of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase-Ca²⁺ (ERK), calmodulin-dependent protein kinase (CAMKII) and cAMP-response element-binding protein (CREB) signalling pathway. Strength exercise was effective against the decrease in the time spent and distance travelled in the target quadrant by STZ-injected mice. Strength exercise was also effective against the reduction of mature BDNF, tropomyosin receptor kinase B and neuronal nuclear antigen (NeuN) hippocampal protein levels in STZ mice. The decrease in the hippocampal ratio of pERK/ERK, pCAMKII/CAMKII and pCREB/CREB induced by STZ was reversed by strength exercise. Strength exercise decreased Bax/Bcl2 ratio in the hippocampus of STZ-injected mice. The present study demonstrates that strength exercise modulated the hippocampal BDNF/ERK-CAMKII/CREB signalling pathway and suppressed STZ-induced spatial memory impairment in mice.     

BDNF—TrkB信号通路与焦虑障碍的产生

BDNF-TrkB信号通路对情绪产生、认知功能和记忆能力都有重要的影响,主要通过PI3-K途径和Ras-MAP激酶途径调节神经元的再生、凋亡及重建。近年来的研究表明,BDNF基因型及其表达量和TrkB受体表达的异常与焦虑障碍的产生有非常密切的关系。本文综述了近年来BDNF-TrkB信号通路及其与焦虑障碍产生的联系等方面的研究进展。     

Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF)

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission by determining the magnitude and duration of serotonergic responses. We have recently described a polymorphism in the 5-HTT gene promoter (5-HTTLPR) which influences the function of the 5-HTT and is associated with several psychiatric disorders. Immortalized B lymphocytes express the 5-HTT, and a B lymphocyte line has been shown to express the receptor for brain-derived neurotrophic factor, trkB. Since brain-derived neurotrophic factor (BDNF) is a specific growth and differentiation factor for serotonergic neurons, we assessed whether BDNF is able to modulate 5-HTT function in B lymphoblasts. Nerve growth factor (NGF), another neurotrophin which acts via the trkA receptor, was also studied. Eight immortalized B lymphoblast lines were generated and genotyped for the 5-HTTLPR. After treatment with BDNF or NGF, 5-HT uptake and proliferation of the cell lines were assessed. Two of the B cell lines showed a dose-dependent reduction of 5-HT uptake after exposure to BDNF. Both of these cell lines were homozygous for the long allele of the 5-HTTLPR. NGF did not influence 5-HT uptake or cellular proliferation in any of the cell lines. Thus, BDNF but not NGF may influence 5-HT uptake in some B lymphocytes. The fact that regulation of the 5-HTT was observed preferentially in cells of the long/long genotype indicates that presence of a short allele confers reduced regulatory capacity on the 5-HTT. In conclusion, B lymphoblasts represent a practical model for functional regulation of the 5-HTT by neurotrophins in serotonergic neurons.     

Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms

The effects of brain-derived neurotrophic factor (BDNF) and cAMP on the neuronal serotoninergic phenotype were studied in primary cultures of E14 rat embryonic rostral raphe. Short treatments (for 18 h) with BDNF or dibutyryl-cAMP induced an almost two-fold increase in the number of serotoninergic neurones and a dramatic extension and ramification of their neurites. These changes were associated with marked increases in the levels of mRNAs encoding the serotonin transporter, the 5-HT1A and 5-HT1B receptors and the BDNF receptor tyrosine kinase B (TrkB). Concomitant blockade of tyrosine kinases by genistein suppressed all the up-regulating effects of BDNF and cAMP on 5-hydroxytryptamine (5-HT) neurones. These findings suggest that an auto-amplifying mechanism underlies the promoting effect of BDNF on the differentiation of serotoninergic neurones through TrkB activation, which is also triggered by cAMP.     

5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling

The 5-hydroxytryptamine(4) (5-HT(4)) receptors have recently emerged as key modulators of learning, memory, and cognitive processes. In neurons, 5-hydroxytryptamine(4) receptors (5-HT(4)Rs) activate cAMP production and protein kinase A (PKA); however, nothing is known about their ability to activate another key signaling pathway involved in learning and memory: the extracellular signal-regulated kinase (ERK) pathway. Here, we show that 5-HT(4)R stimulation, in primary neurons, produced a potent but transient activation of the ERK pathway. Surprisingly, this activation was mostly PKA independent. Similarly, using pharmacological, genetic, and molecular tools, we observed that 5-HT(4)Rs in human embryonic kidney 293 cells, activated the ERK pathway in a G(s)/cAMP/PKA-independent manner. We also demonstrated that other classical G proteins (G(q)/G(i)/G(o)) and associated downstream messengers were not implicated in the 5-HT(4)R-activated ERK pathway. The 5-HT(4)R-mediated ERK activation seemed to be dependent on Src tyrosine kinase and yet totally independent of beta-arrestin. Immunocytofluorescence revealed that ERK activation by 5-HT(4)R was restrained to the plasma membrane, whereas p-Src colocalized with the receptor and carried on even after endocytosis. This phenomenon may result from a tight interaction between 5-HT(4)R and p-Src detected by coimmunoprecipitation. Finally, we confirmed that the main route by which 5-HT(4)Rs activate ERKs in neurons was Src dependent. Thus, in addition to classical cAMP/PKA signaling pathways, 5-HT(4)Rs may use ERK pathways to control memory process.     

Role for brain-derived neurotrophic factor in learning and memory

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.     

Reduced brain-derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice

Brain-derived neurotrophic factor (BDNF) regulates monoamine neuronal growth, survival and function in development and throughout adulthood. At 18 months of age, mice with constitutive reductions in BDNF expression show decreased serotonin innervation in the hippocampus compared with age-matched wildtype mice. It is not known, however, whether age-accelerated loss of serotonergic innervation in BDNF(+/-) mice occurs in other brain regions, advances beyond 18 months or is associated with alterations in other neurotransmitter systems. In this study, immunocytochemistry was used to assess serotonergic and catecholaminergic innervation in 26-month-old BDNF(+/-) mice. Age-related loss of serotonin axons in the hippocampus was potentiated in BDNF(+/-) mice compared with wildtype mice at this late age, particularly in the CA1 subregion. By contrast, aging BDNF(+/-) mice showed increased serotonin innervation of the basomedial nucleus of the amygdala. In the noradrenergic system, BDNF(+/-) mice showed reduced numbers of cell bodies and fibers in the locus coeruleus compared with age-matched wildtype mice, whereas no changes were observed in dopaminergic innervation with respect to genotype. In vivo zero net flux microdialysis in awake mice showed a significant decrease in extracellular serotonin levels in the hippocampus in BDNF(+/-) mice at 20 months of age. Thus, reduced BDNF is associated with altered serotonergic and noradrenergic innervation in aging mice and, in particular, with accelerated loss of serotonergic innervation to the hippocampus that is manifest as a decrease in basal neurotransmission.     

普拉克索联合补肾活血通络胶囊治疗老年帕金森病的临床疗效及对血清5-HT、BDNF、S-100β水平的影响

目的:分析普拉克索联合补肾活血通络胶囊治疗老年帕金森病的临床效果及对血清5-羟色胺(5-HT)、脑源性神经营养因子(BDNF)、S-100β水平的影响。方法:选择我院2014年12月~2016年12月收治的96例老年帕金森病患者,按随机数字表法分为对照组和研究组,每组48例。对照组采用普拉克索治疗,研究组基于对照组加以补肾活血通络胶囊治疗。观察并比较两组临床疗效指标统一帕金森病评分量表Ⅰ(unified parkinson’s disease rating scale,UPDRS)Ⅰ、UPDRSⅡ、UPDRSⅢ、UPDRSⅣ、总UPDRS,血清5-HT、BDNF、S-100β水平的变化及不良反应的发生情况。结果:治疗后,研究组总有效率为87.50%,显著高于对照组(64.58%,P<0.05)。两组治疗后的UPDRSⅠ、UPDRSⅡ、UPDRSⅢ、UPDRSⅣ、总UPDRS、血清S-100β水平均较治疗前显著下降,且研究组以上指标均明显低于对照组。两组治疗后的血清5-HT、BDNF水平均较治疗前明显上升,且研究组以上指标均明显高于对照组(P<0.05)。研究组不良反应发生率显著低于对照组(P<0.05)。结论:普拉克索联合补肾活血通络胶囊治疗治疗老年帕金森病的临床效果优于单用普拉克索,可能与其显著提高血清5-HT及BDNF表达并降低S-100β水平有关。     

Dcf1 Affects Memory and Anxiety by Regulating NMDA and AMPA Receptors

The hippocampus is critical for memory and emotion and both N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors are known to contribute for those processes. However, the underlying molecular mechanisms remain poorly understood. We have previously found that mice undergo memory decline upon dcf1 deletion through ES gene knockout. In the present study, a nervous system-specific dcf1 knockout (NKO) mouse was constructed, which was found to present severely damaged neuronal morphology. The damaged neurons caused structural abnormalities in dendritic spines and decreased synaptic density. Decreases in hippocampal NMDA and AMPA receptors of NKO mice lead to abnormal long term potentiation (LTP) at DG, with significantly decreased performance in the water maze, elevated- plus maze, open field and light and dark test. Investigation into the underlying molecular mechanisms revealed that dendritic cell factor 1 (Dcf1) contributes for memory and emotion by regulating NMDA and AMPA receptors. Our results broaden the understanding of synaptic plasticity’s role in cognitive function, thereby expanding its known list of functions.

     

Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) is critical for the function and survival of neurons that degenerate in the late stage of Alzheimer's disease (AD). There are two forms of BDNF, the BDNF precursor (proBDNF) and mature BDNF, in human brain. Previous studies have shown that BDNF mRNA and protein, including proBDNF, are dramatically decreased in end-stage AD brain. To determine whether this BDNF decrease is an early or late event during the progression of cognitive decline, we used western blotting to measure the relative amounts of BDNF proteins in the parietal cortex of subjects clinically classified with no cognitive impairment (NCI), mild cognitive impairment (MCI) or mild to moderate AD. We found that the amount of proBDNF decreased 21 and 30% in MCI and AD groups, respectively, as compared with NCI, consistent with our previous results of a 40% decrease in end-stage AD. Mature BDNF was reduced 34 and 62% in MCI and AD groups, respectively. Thus, the decrease in mature BDNF and proBDNF precedes the decline in choline acetyltransferase activity which occurs later in AD. Both proBDNF and mature BDNF levels were positively correlated with cognitive measures such as the Global Cognitive Score and the Mini Mental State Examination score. These results demonstrate that the reduction of both forms of BDNF occurs early in the course of AD and correlates with loss of cognitive function, suggesting that proBDNF and BDNF play a role in synaptic loss and cellular dysfunction underlying cognitive impairment in AD.     

Maternal Exercise during Pregnancy Increases BDNF Levels and Cell Numbers in the Hippocampal Formation but Not in the Cerebral Cortex of Adult Rat Offspring

Clinical evidence has shown that physical exercise during pregnancy may alter brain development and improve cognitive function of offspring. However, the mechanisms through which maternal exercise might promote such effects are not well understood. The present study examined levels of brain-derived neurotrophic factor (BDNF) and absolute cell numbers in the hippocampal formation and cerebral cortex of rat pups born from mothers exercised during pregnancy. Additionally, we evaluated the cognitive abilities of adult offspring in different behavioral paradigms (exploratory activity and habituation in open field tests, spatial memory in a water maze test, and aversive memory in a step-down inhibitory avoidance task). Results showed that maternal exercise during pregnancy increased BDNF levels and absolute numbers of neuronal and non-neuronal cells in the hippocampal formation of offspring. No differences in BDNF levels or cell numbers were detected in the cerebral cortex. It was also observed that offspring from exercised mothers exhibited better cognitive performance in nonassociative (habituation) and associative (spatial learning) mnemonic tasks than did offspring from sedentary mothers. Our findings indicate that maternal exercise during pregnancy enhances offspring cognitive function (habituation behavior and spatial learning) and increases BDNF levels and cell numbers in the hippocampal formation of offspring.     

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7−/−) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [³H]glutamate in P2rx7+/+ but not P2rx7−/− mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7−/− mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7−/− mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR_1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7−/− mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7−/− mice, which accompanied the increased uptake of [³H]5-HT and an elevated number of [³H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7−/− mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7−/− mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus.