BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats

Kramár, Enikö A.; Chen, Lulu Y.; Lauterborn, Julie C.; Simmons, Danielle A.; Gall, Christine M.; Lynch, Gary

doi:10.1016/j.neurobiolaging.2010.06.008

Cited by 59 publications

(46 citation statements)

References 79 publications

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“…In addition, previous studies showed that regular ampakine administration would increase the expression of BDNF. Considering that ampakines can also cross the blood-brain barrier, are bioactive orally and improve cognitive function without obvious side effects, they are of great potential and in fact have been partially proved to be candidate for a range of neurological disability and disturbances, including Alzheimer's disease and Huntington's disease [58,[61][62][63] . We hypothesize that ampakines are beneficial to the neurocognitive problems found in OSA by its action in elevating endogenous BDNF level in the brain.…”

Section: Future Directionsmentioning

confidence: 99%

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Xie

Yung

2012

Acta Pharmacol Sin

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Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated.

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Section: Future Directionsmentioning

confidence: 99%

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Xie

Yung

2012

Acta Pharmacol Sin

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“…There is now a large literature demonstrating disturbances in spine morphology and signaling cascades at excitatory synapses in animal models of cognitive disability (Belichenko et al, 2007;Kramar et al, 2012), including disorders on the autism spectrum (Chen et al, 2010;Hung et al, 2008;Seese et al, 2012;Tropea et al, 2009). Learning and executive functions are impaired in BTBR mice (Amodeo et al, 2012;Lipina and Roder, 2013;MacPherson et al, 2008;Ribeiro et al, 2013;Rutz and Rothblat, 2012;Silverman et al, 2013;Yang et al, 2012), but thorough analyses of associated synaptic abnormalities and evidence for pharmacological normalization of these measures are lacking.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Seese

Maske

Lynch

et al. 2014

Neuropsychopharmacol

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A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T þ Itpr3 tf /J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2 þ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

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“…Thus, the compounds prolong the opening of ligand bound AMPARs and increase the size and duration of fast, excitatory post-synaptic potentials (EPSPs) (Lynch, 2006). Recent work has shown that a relatively short series of daily ampakine injections rescues hippocampal synaptic plasticity in rodent models of aging (Rex et al, 2006), low estrogen levels (Kramar et al, 2010) and Huntington’s Disease (HD) (Simmons et al, 2009). In the latter case, treatment of CAG140 knock-in mice with a short half-life ampakine (CX929) also reduced memory deficits associated with early stage HD.…”

Section: Introductionmentioning

confidence: 99%

Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice

Simmons¹,

Mehta²,

Lauterborn³

et al. 2011

Neurobiology of Disease

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Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington’s Disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4–7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced the area of intranuclear huntingtin aggregates in R6/2 striatum by 36%. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.

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BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats

Cited by 59 publications

References 79 publications

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism

Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice

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