Article

Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: Involvement of phospholipaseCγ activity and glutamate receptor expression

Departament de Biologia Cellular i Anatomia Patològica, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain.
Neuroscience (Impact Factor: 3.33). 12/2008; 158(4):1234-50. DOI: 10.1016/j.neuroscience.2008.11.024
Source: PubMed

ABSTRACT The involvement of brain-derived neurotrophic factor (BDNF) in cognitive processes and the decrease in its expression in Huntington's disease suggest that this neurotrophin may play a role in learning impairment during the disease progression. We therefore analyzed the onset and severity of cognitive deficits in two different mouse models with the same mutant huntingtin but with different levels of BDNF (R6/1 and R6/1:BDNF+/- mice). We observed that BDNF modulates cognitive function in different learning tasks, even before the onset of motor symptoms. R6/1:BDNF+/- mice showed earlier and more accentuated cognitive impairment than R6/1 mice at 5 weeks of age in discrimination learning; at 5 weeks of age in procedural learning; and at 9 weeks of age in alternation learning. At the earliest age at which cognitive impairment was detected, electrophysiological analysis was performed in the hippocampus. All mutant genotypes showed reduced hippocampal long term potentiation (LTP) with respect to wild type but did not show differences between them. Thus, we evaluated the involvement of BDNF-trkB signaling and glutamate receptor expression in the hippocampus of these mice. We observed a decrease in phospholipaseCgamma activity, but not ERK, in R61, BDNF+/- and R6/1:BDNF+/- hippocampus at the age when LTP was altered. However, a specific decrease in the expression of glutamate receptors NR1, NR2A and GluR1 was detected only in R6/1:BDNF+/- hippocampus. Therefore, these results show that BDNF modulates the learning and memory alterations induced by mutant huntingtin. This interaction leads to intracellular changes, such as specific changes in glutamate receptors and in BDNF-trkB signaling through phospholipaseCgamma.

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Available from: Giralt Albert, Aug 13, 2015
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    • "Here, we showed for the first time that R6/1 mice had impaired LTP in vivo, when induced by HFS at the Schaffer collateral pathway. These results are in accordance with previous studies performed in HD hippocampal slices (Giralt et al., 2009; Murphy et al., 2000; Usdin et al., 1999). "
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    ABSTRACT: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. Copyright © 2014. Published by Elsevier Inc.
    Neurobiology of Disease 11/2014; 74C:41-57. DOI:10.1016/j.nbd.2014.11.004 · 5.20 Impact Factor
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    • "Effects of the HD mutation and 5 days of CORT treatment on hippocampal BDNF and TrkB levels as well as hippocampal cell proliferation High levels of exogenous CORT treatment reduce mRNA and protein levels of the neurotrophin, brain-derived neurotrophic factor (BDNF) in the hippocampus (Jacobsen and Mørk, 2006). In R6/1 HD mice, reduced levels of hippocampal BDNF were previously associated with impaired learning (Giralt et al., 2009). We therefore quantified hippocampal BDNF levels after 5 days of CORT treatment. "
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    ABSTRACT: Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation in the huntingtin gene. Lifestyle factors, such as lack of activity may contribute to the variability in the age of disease onset. Therefore, better understanding of environmental modifiers may uncover potential therapeutic approaches to delay disease onset and progression. Recent data suggest that HD patients and transgenic mouse models show a dysregulated stress response. In this present study, we elevated stress hormone levels through oral corticosterone (CORT) treatment and assessed its impact on the development of motor impairment and cognitive deficits using the R6/1 transgenic mouse model of HD. We found that CORT consumption did not alter rotarod performance of R6/1 HD or wild-type (WT) littermates. However, the onset of hippocampal-dependent Y-maze deficits was accelerated in male R6/1 mice by 5 days of CORT treatment, whereas short term memory of WT and female R6/1 mice was unaffected. We then further investigated the male HD susceptibility to CORT by measuring TrkB activation, BDNF and glucocorticoid receptor expression as well as the level of cell proliferation in the hippocampus. CORT treatment increased the levels of phosphorylated TrkB in male R6/1 mice only. There were no effects of CORT on hippocampal BDNF protein or mRNA levels; nor on expression of the glucocorticoid receptors in any group. Hippocampal cell proliferation was decreased in male R6/1 mice and this was further reduced in CORT-drinking male R6/1 mice. Female mice (WT and R6/1) appeared to be protected from the impacts of CORT treatment in all our hippocampal measures. Overall, our data demonstrate that treatment with corticosterone is able to modulate the onset of HD symptomatology. We present the first evidence of a male-specific vulnerability to stress impacting on the development of short-term memory deficits in HD. More generally, we found that female mice were protected from the detrimental effects of CORT treatment on a variety of hippocampus-based measures. Hippocampal plasticity and memory in HD may be more susceptible to the impacts of stress in a sex-dependent manner. We propose clinical investigations of stress as a key environmental modifier of HD symptom onset.
    Neurobiology of Disease 09/2014; 69. DOI:10.1016/j.nbd.2014.05.004 · 5.20 Impact Factor
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    • "Consistent with this, epilepsy is markedly inhibited in trkB PLC/PLC knock-in mice lacking PLCg-1docking sites in TrkB (He et al., 2010). On the other hand, phosphorylation of PLC-g1 is decreased in HD models (Giralt et al., 2009), and the expression levels of BDNF and TrkB are reduced in humans and mice with HD (Ferrer et al., 2000; Gines et al., 2006; Zuccato et al., 2008). Moreover, activation of PLC-g1 induces activation of CREB, which is required to increase BDNF, for a long-term anti-depressive effect in the hippocampus (Minichiello et al., 2002; Nestler et al., 2002; Yagasaki et al., 2006). "
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    ABSTRACT: The roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-β and PLC-γ, are directly activated by receptor activation, unlike other secondary PLCs (PLC-ɛ, PLC-δ1, and PLC-η1). PLC-β isozymes are activated by G protein couple receptor and PLC-γ isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology.
    08/2013; 53. DOI:10.1016/j.jbior.2013.08.003
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