Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP

Saarelainen, Tommi; Pussinen, Raimo; Koponen, Eija; Alhonen, Leena; Wong, Garry; Sirviö, Jouni; Ċastrén, Eero

doi:10.1002/1098-2396(200010)38:1<102::aid-syn11>3.0.co;2-k

Cited by 84 publications

(45 citation statements)

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“…Disruption of BDNF expression by use of antisense oligonucleotides [17,18], in heterozygous BDNF knockout animals [19] or by use of anti-BDNF antibodies [20] caused severe impairment in spatial memory and learning. Similarly impaired learning was evident in the conditional TrkB knockout [21] and in mice overexpressing the truncated form of TrkB [22].…”

Section: Synaptic Plasticitysupporting

confidence: 88%

Clinical relevance of the neurotrophins and their receptors

2006

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The neurotrophins are growth factors required by discrete neuronal cell types for survival and maintenance, with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal. This review examines their role in diverse disease states, including Alzheimer's disease, depression, pain and asthma. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed. Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation. Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models. Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF. Conversely, in Alzheimer's disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process. This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.

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Section: Synaptic Plasticitysupporting

confidence: 88%

Clinical relevance of the neurotrophins and their receptors

2006

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“…In parallel, blocking BDNF synthesis or TrkB availability has been shown to impair LTM formation: BDNF+/-mice are impaired in Morris water maze acquisition (Linnarsson, Bjorklund, and Ernfors, 1997) and contextual fear conditioning (Liu, Lyons, Mamounas, and Thompson, 2004); deletion of the TrkB gene in the forebrain results in severe behavioral deficits in a spatial water maze task and moderate deficits in a radial arm maze task (Minichiello et al, 1999); inhibition of BDNF mRNA expression via hippocampal infusion of BDNF antisense oligos or anti-BDNF antibody before training blocks acquisition in inhibitory avoidance and radial arm maze tasks (Alonso et al, 2002;Ma et al, 1998;Mizuno et al, 2000). Genetic and pharmacological manipulations of BDNF signaling prior to training have also been shown to impair LTM (Gorski, Balogh, Wehner, and Jones, 2003;Heldt, Stanek, Chhatwal, and Ressler, 2007;Johnston, Clements, and Rose, 1999;Koponen, Voikar, Riekki, Saarelainen, Rauramaa, Rauvala, Taira, and Castren, 2004;Monteggia, Barrot, Powell, Berton, Galanis, Gemelli, Meuth, Nagy, Greene, and Nestler, 2004;Mu, Li, Yao, and Zhou, 1999;Saarelainen, Pussinen, Koponen, Alhonen, Wong, Sirvio, and Castren, 2000).…”

Section: Formation (Acquisition or Encoding) Of Ltmmentioning

confidence: 99%

BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory?

Lü

Christian

2008

Neurobiology of Learning and Memory

672

464

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It is generally believed that late-phase long-term potentiation (L-LTP) and long-term memory (LTM) require new protein synthesis. Although the full complement of proteins mediating the long-lasting changes in synaptic efficacy have yet to be identified, several lines of evidence point to a crucial role for activity-induced brain derived neurotrophic factor (BDNF) expression in generating sustained structural and functional changes at hippocampal synapses thought to underlie some forms of LTM. In particular, BDNF is sufficient to induce the transformation of early to late phase LTP in the presence of protein synthesis inhibitors, and inhibition of BDNF signaling impairs LTM. Despite solid evidence for a critical role of BDNF in L-LTP and LTM, many issues are not resolved. Given that BDNF needs to be processed in Golgi outposts localized at the branch point of one or few dendrites, a conceptually challenging problem is how locally synthesized BDNF in dendrites could ensure synapse-specific modulation of L-LTP. An interesting alternative is that BDNF-TrkB signaling is involved in synaptic tagging, a prominent hypothesis that explains how soma-derived protein could selectively modulate the tetanized (tagged) synapse. Finally, specific roles of BDNF in the acquisition, retention or extinction of LTM remain to be established.

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“…BDNF also regulates activity-dependent changes in synaptic plasticity, such as long-term potentiation in the hippocampus, which are fundamental to memory formation (e.g., Kuczewski, Porcher, Lessmann, Medina, & Gaiarsa, 2009;Berkinschtein et al, 2008). Consistent with these assertions, pharmacological and genetic deprivation of BDNF in animals induce deficits in hippocampal-dependent spatial memory and other forms of associative learning (e.g., Hall, Thomas, & Everitt, 2000;Saarelainen et al, 2000;Linnarsson, Bjorklund, & Ernfors, 1997).…”

Section: Introductionmentioning

confidence: 99%

Ebbinghaus Revisited: Influences of the BDNF Val66Met Polymorphism on Backward Serial Recall Are Modulated by Human Aging

Chicherio

Nyberg

et al. 2010

Journal of Cognitive Neuroscience

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Abstract■ The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve-a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age. ■

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Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP

Cited by 84 publications

References 20 publications

Clinical relevance of the neurotrophins and their receptors

Clinical relevance of the neurotrophins and their receptors

BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory?

Ebbinghaus Revisited: Influences of the BDNF Val66Met Polymorphism on Backward Serial Recall Are Modulated by Human Aging

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