The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity,anxiety, and memory deficits

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long‐term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety‐like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short‐term EE for 10 days can overcome restraint stress–induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short‐term EE on chronic stress–induced impaired LTP, working memory, and anxiety‐like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1‐LTP, increased anxiety‐like symptoms in elevated plus maze, and impaired working memory in T‐maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc.     

Disruption of hippocampus‐regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP

The brain‐specific Ras/Rap‐GTPase activating protein (SynGAP) is a prime candidate linking N‐methyl‐d ‐aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience‐dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG^+/?), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG^+/? mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T‐maze. In the non‐cognitive domain, SG^+/? mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG^+/? mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non‐cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin‐positive interneurons in the hippocampus and doublecortin‐positive neurons in the dentate gyrus of adult SG^+/? mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.     

Chronic methamphetamine exposure produces a delayed,long‐lasting memory deficit

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long‐term deficits in short‐term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short‐term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short‐term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH‐exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short‐term as well as long‐term consequences of methamphetamine exposure. Synapse 67:245–257, 2013. © 2012 Wiley Periodicals, Inc.     

Effect of brain‐derived neurotrophic factor haploinsufficiency on stress‐induced remodeling of hippocampal neurons

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity‐dependent manner, as a mediator of the stress‐induced dendritic remodeling. The analysis of Golgi‐impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF^±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF^± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF^± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. © 2010 Wiley‐Liss, Inc.     

BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies.

BACKGROUND: Changes in densities and in the morphology of dendritic spines in the hippocampus are linked to hippocampal long-term potentiation (LTP), spatial learning, and depression. Decreased brain-derived neurotrophic factor (BDNF) levels seem to contribute to depression. Through its receptor trkB, BDNF is also involved in hippocampal LTP and hippocampus-dependent learning. Conditionally gene-targeted mice in which the ablation of trkB is restricted to the forebrain and occurs only during postnatal development display impaired learning and LTP. METHODS: To examine whether there is a link among impaired hippocampal synaptic plasticity, altered spines, and trkB receptors, we performed a quantitative analysis of spine densities and spine length in the hippocampal area CA1 and the dentate gyrus in conditional mutant mice (trkB(lox/lox)CaMKII-CRE mice). TrkB protein and mRNA levels were assayed using Western blot and in situ hybridization analysis. RESULTS: Fifteen-week-old mutant mice exhibit specific reductions in spine densities and a significant increase in spine length of apical and basal dendrites in area CA1. These alterations correlate with a time- and region-specific reduction in full-length trkB mRNA in the hippocampus. CONCLUSIONS: TrkB functions in structural remodeling of hippocampal dendritic spines, which in turn may affect synaptic transmission and plasticity.     

Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice

Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IκB kinase β, the main activating kinase in the inducible NF‐κB pathway, selectively in myeloid lineage cells (mIKKβKO) or excitatory neurons (nIKKβKO) to measure synaptic strength at hippocampal Schaffer collaterals during long‐term potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKβKO mice showed less Iba1‐immunoreactivity, and brain IL‐1β mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3‐CA1 synapse in mIKKβKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKβKO mice showed normal basic synaptic transmission and LTP induction but impairments in late LTP. To understand the consequences of such impairments in synaptic plasticity for learning and memory, we measured CA1 fEPSPs in behaving mice during instrumental conditioning. IKKβ was not necessary in either microglia or neurons for mice to learn lever‐pressing (appetitive behavior) to obtain food (consummatory behavior) but was required in both for modification of their hippocampus‐dependent appetitive, not consummatory behavior. Our results show that microglia, through IKKβ and therefore NF‐κB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKβ, are necessary for animals to modify hippocampus‐driven behavior during associative learning. GLIA 2015;63:549–566     

Hippocampal changes in mice lacking an active prohormone convertase 2

Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.     

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11–18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22–31) performed one two‐trial Y‐maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long‐term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine‐exposed juvenile offspring. The morphine group also showed poorer performance for the Y‐maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP‐spike potentiation. Then a loss of GABA‐containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy. © 2008 Wiley‐Liss, Inc.     

Acute stress disrupts paired pulse facilitation and long‐term potentiation in rat dorsal hippocampus through activation of glucocorticoid receptors

Cognitive functions such as learning and memory are widely believed to depend on patterns of short‐ and long‐term synaptic plasticity. Factors, such as acute stress, which affect learning and memory, may do so by altering patterns of synaptic plasticity in distinct neural circuits. Numerous studies have examined the effects of acute stress on long‐term synaptic plasticity; however, few have examined its influence on short‐term plasticity. The present experiments directly assessed the effects of acute stress on short‐term synaptic plasticity as measured by paired pulse facilitation (PPF) of excitatory postsynaptic potentials recorded from rat dorsal hippocampus (dHip) in vivo. Long‐term potentiation (LTP) was also examined. Acute stress induced by exposure to an elevated platform impaired PPF and LTP in the dHip. Pretreatment of rats exposed to stress with mifepristone (RU38486; 10 mg kg⁻¹) blocked the stress‐induced impairment of both PPF and LTP. These data demonstrate that activation of glucocorticoid receptors during acute stress disrupts normal patterns of both PPF and LTP in the dHip. © 2009 Wiley‐Liss, Inc.     

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle.The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF^Val/Val) and homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF^Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF^Met/Met mice compared to BDNF^Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF^Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF^Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF^Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.     

Brain-derived neurotrophic factor rapidly increases NMDA receptor channel activity through Fyn-mediated phosphorylation

Brain-derived neurotrophic factor (BDNF) is a potent modulator of hippocampal synaptic plasticity. Previously, we found that one of the targets of BDNF modulation is NR2B-containing NMDA receptors. Furthermore, exposure to the trophin rapidly increases NMDA receptor activity and enhances tyrosine phosphorylation of NR2B in cortical and hippocampal postsynaptic densities (PSDs), potentially linking receptor phosphorylation to synaptic plasticity. To define the specific NR2B residue(s) regulated by BDNF, we focused on tyrosine 1472, phosphorylation of which increases after LTP. BDNF rapidly increased phosphorylation in cortical PSDs. The tyrosine kinase Fyn is critical since BDNF-dependent phosphorylation was abolished in Fyn knockout mice. Single-channel patch clamp recordings showed that Fyn is required for the increase in NMDA receptor activity elicited by BDNF. Collectively, our results suggest that BDNF enhances phosphorylation of NR2B tyrosine 1472 through activation of Fyn, leading to alteration of NMDA receptor activity and increased synaptic transmission.     

Brain-derived neurotrophic factor in amygdala-dependent learning.

The neurotrophin brain-derived neurotrophic factor (BDNF) has recently emerged as a possible molecular mediator of activity-dependent synaptic plasticity underlying learning and memory. Long-term potentiation (LTP) within the hippocampus and hippocampally dependent behaviors has been the primary model for examining the role of BDNF in learning and memory. However, these studies are limited by an incomplete understanding of the complex behavioral function of hippocampal circuitry, making it difficult to unravel the molecular machinery responsible for the formation and storage of these memories. In contrast, the amygdala and its role in Pavlovian fear conditioning promise to provide us with new insights into the mechanisms of BDNF-mediated synaptic plasticity during the learning and memory process. This article reviews the different levels of research on BDNF in learning and memory. The focus is primarily on the use of Pavlovian fear conditioning as a learning model that allows for the examination of the role of BDNF in the amygdala, following a single learning session and within a well-understood neural circuit.     

Neurotrophins and hippocampal synaptic transmission and plasticity.

Neurotrophins are traditionally thought to be secretory proteins that regulate long-term survival and differentiation of neurons. Recent studies have revealed a previously unexpected role for neurotrophins in synaptic development and plasticity in diverse neuronal populations. In this review, we focus on the synaptic function of brain-derived neurotrophic factor (BDNF) in the hippocampus. Although a variety of in vitro experiments have shown the ability of BDNF to acutely modulate synaptic transmission, whether BDNF truly potentiates basal synaptic transmission in hippocampal neurons remains controversial. More consistent evidence has been obtained for the role of BDNF in long-term potentiation (LTP), a cellular model for learning and memory. BDNF also potentiates high frequency transmission by modulating the number of docked vesicles and the levels of the vesicle protein synaptobrevin and synaptophysin at the CA1 synapses. Both pre- and postsynaptic effects of BDNF have been demonstrated. Recent studies have begun to address the role of BDNF in late-phase LTP and in the development of hippocampal circuit. BDNF and other neurotrophins may represent a new class of neuromodulators that regulate neuronal connectivity and synaptic efficacy. J. Neurosci. Res. 58:76-87, 1999. Published 1999 Wiley-Liss, Inc.     

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

Recent evidence suggests that activity‐regulated cytoskeleton associated protein (Arc) and brain‐derived neurotrophic factor (BDNF) are key players in the cellular mechanisms that trigger synaptic changes and memory consolidation. Cholinergic deafferentiation of hippocampus has been largely shown to induce memory impairments in different behavioral tasks. However, the mechanisms underlying cholinergic‐induced memory formation remain unclear. The role of hippocampal cholinergic denervation on synaptic consolidation and further acquisition of spatial memory was hereby examined by analyzing Arc and BDNF in standard environment and after behavioral training in Morris water maze (MWM). In standard environment, a cholinergic hypofunction induced by the toxin ¹⁹²IgG‐saporin led to significant decreases in Arc protein and mRNA as well as in BDNF. Lesioned rats subjected to MWM showed a worse acquisition performance that was reversed after galantamine treatment. Recovery of memory acquisition was accompanied by normalization of Arc and BDNF levels in hippocampus. Stimulation of muscarinic, but not nicotinic receptors, in hippocampal primary neurons caused a rapid induction of Arc production. These data suggest that cholinergic denervation of hippocampus leads to deficits in muscarinic‐dependent induction of Arc and a subsequent impairment of spatial memory acquisition. © 2010 Wiley‐Liss, Inc.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

Tg2576 mice are widely used to study amyloid‐dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long‐term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3‐, 10‐, and 15‐month‐old wild‐type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short‐ and long‐term plasticity by inducing paired‐pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15‐month‐old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L‐type voltage‐gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. © 2015 Wiley Periodicals, Inc.     

PINK1 heterozygous mutations induce subtle alterations in dopamine‐dependent synaptic plasticity

Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog‐induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non‐manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1^+/?) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long‐term potentiation (LTP), whereas long‐term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1^+/? mice compared with control mice, suggesting that a decrease in stimulus‐evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease‐modifying therapies. © 2013 International Parkinson and Movement Disorder Society