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Effects of PI3Kγ overexpression in the hippocampus on synaptic plasticity and spatial learning.

Choi JH, Park P, Baek GC, Sim SE, Kang SJ, Lee Y, Ahn SH, Lim CS, Lee YS, Collingridge GL, Kaang BK - Mol Brain (2014)

Bottom Line: To further examine the role of PI3Kγ in synaptic plasticity and hippocampus-dependent behavioral tasks we overexpressed p110γ, the catalytic subunit of PI3Kγ, in the hippocampal CA1 region.In contrast, long-term potentiation (LTP) and contextual fear memory were not affected by p110γ overexpression.These results, together with the previous knockout study, suggest that a critical level of PI3Kγ in the hippocampus is required for successful induction of LTD and normal learning.

View Article: PubMed Central - PubMed

ABSTRACT
Previous studies have shown that a family of phosphoinositide 3-kinases (PI3Ks) plays pivotal roles in the brain; in particular, we previously reported that knockout of the γ isoform of PI3K (PI3Kγ) in mice impaired synaptic plasticity and reduced behavioral flexibility. To further examine the role of PI3Kγ in synaptic plasticity and hippocampus-dependent behavioral tasks we overexpressed p110γ, the catalytic subunit of PI3Kγ, in the hippocampal CA1 region. We found that the overexpression of p110γ impairs NMDA receptor-dependent long-term depression (LTD) and hippocampus-dependent spatial learning in the Morris water maze (MWM) task. In contrast, long-term potentiation (LTP) and contextual fear memory were not affected by p110γ overexpression. These results, together with the previous knockout study, suggest that a critical level of PI3Kγ in the hippocampus is required for successful induction of LTD and normal learning.

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Impaired induction of p38 MAPK phosphorylation by chemical LTD in p110γ-overexpressed hippocampal CA1 region. (A) Representative phospho/total p38 MAPK western blot from tdTomato- or p110γ-overexpressed slices after chemical LTD induction (NMDA treatment). (B) Normalized basal phosphorylation level of p38 MAPK from tdTomato- or p110γ-overexpressed slices. (C) Normalized phosphorylation level of p38 MAPK from tdTomato-overexpressed slices after chemical LTD induction (n = 5, p <0.05, paired Student’s t-test). (D) Normalized phosphorylation level of p38 MAPK from p110γ-overexpressed slices, after chemical LTD induction (n = 5, NS, paired Student’s t-test).
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Fig2: Impaired induction of p38 MAPK phosphorylation by chemical LTD in p110γ-overexpressed hippocampal CA1 region. (A) Representative phospho/total p38 MAPK western blot from tdTomato- or p110γ-overexpressed slices after chemical LTD induction (NMDA treatment). (B) Normalized basal phosphorylation level of p38 MAPK from tdTomato- or p110γ-overexpressed slices. (C) Normalized phosphorylation level of p38 MAPK from tdTomato-overexpressed slices after chemical LTD induction (n = 5, p <0.05, paired Student’s t-test). (D) Normalized phosphorylation level of p38 MAPK from p110γ-overexpressed slices, after chemical LTD induction (n = 5, NS, paired Student’s t-test).

Mentions: We next examined the effect of p110γ overexpression on the downstream pathway involved in NMDAR-LTD. p38 MAPK is known to be involved in NMDAR-LTD through Rap1 signaling pathway and active Rap1 directly binds to p110γ [10-12]. In our previous study, we found that p110γ deletion reduced the phosphorylation of p38 MAPK induced by chemical LTD [9]. We performed similar chemical LTD experiments with tdTomato- or p110γ-overexpressing hippocampal slices. We first confirmed that p110γ overexpression itself did not affect the basal phosphorylation level of p38 MAPK (n = 5, Figure 2A, B). The phosphorylation of p38 MAPK (p-p38) was significantly increased in response to the chemical LTD induction in the tdTomato-expressing group (Figure 2A, C). However, the increase in p38 MAPK phosphorylation associated with chemical LTD was impaired in p110γ-overexpressing group (Figure 2A, D). These results support the finding that NMDAR-LTD is impaired by p110γ overexpression and suggest that this might be due to impairment in p38 MAPK signaling.Figure 2


Effects of PI3Kγ overexpression in the hippocampus on synaptic plasticity and spatial learning.

Choi JH, Park P, Baek GC, Sim SE, Kang SJ, Lee Y, Ahn SH, Lim CS, Lee YS, Collingridge GL, Kaang BK - Mol Brain (2014)

Impaired induction of p38 MAPK phosphorylation by chemical LTD in p110γ-overexpressed hippocampal CA1 region. (A) Representative phospho/total p38 MAPK western blot from tdTomato- or p110γ-overexpressed slices after chemical LTD induction (NMDA treatment). (B) Normalized basal phosphorylation level of p38 MAPK from tdTomato- or p110γ-overexpressed slices. (C) Normalized phosphorylation level of p38 MAPK from tdTomato-overexpressed slices after chemical LTD induction (n = 5, p <0.05, paired Student’s t-test). (D) Normalized phosphorylation level of p38 MAPK from p110γ-overexpressed slices, after chemical LTD induction (n = 5, NS, paired Student’s t-test).
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Related In: Results  -  Collection

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Fig2: Impaired induction of p38 MAPK phosphorylation by chemical LTD in p110γ-overexpressed hippocampal CA1 region. (A) Representative phospho/total p38 MAPK western blot from tdTomato- or p110γ-overexpressed slices after chemical LTD induction (NMDA treatment). (B) Normalized basal phosphorylation level of p38 MAPK from tdTomato- or p110γ-overexpressed slices. (C) Normalized phosphorylation level of p38 MAPK from tdTomato-overexpressed slices after chemical LTD induction (n = 5, p <0.05, paired Student’s t-test). (D) Normalized phosphorylation level of p38 MAPK from p110γ-overexpressed slices, after chemical LTD induction (n = 5, NS, paired Student’s t-test).
Mentions: We next examined the effect of p110γ overexpression on the downstream pathway involved in NMDAR-LTD. p38 MAPK is known to be involved in NMDAR-LTD through Rap1 signaling pathway and active Rap1 directly binds to p110γ [10-12]. In our previous study, we found that p110γ deletion reduced the phosphorylation of p38 MAPK induced by chemical LTD [9]. We performed similar chemical LTD experiments with tdTomato- or p110γ-overexpressing hippocampal slices. We first confirmed that p110γ overexpression itself did not affect the basal phosphorylation level of p38 MAPK (n = 5, Figure 2A, B). The phosphorylation of p38 MAPK (p-p38) was significantly increased in response to the chemical LTD induction in the tdTomato-expressing group (Figure 2A, C). However, the increase in p38 MAPK phosphorylation associated with chemical LTD was impaired in p110γ-overexpressing group (Figure 2A, D). These results support the finding that NMDAR-LTD is impaired by p110γ overexpression and suggest that this might be due to impairment in p38 MAPK signaling.Figure 2

Bottom Line: To further examine the role of PI3Kγ in synaptic plasticity and hippocampus-dependent behavioral tasks we overexpressed p110γ, the catalytic subunit of PI3Kγ, in the hippocampal CA1 region.In contrast, long-term potentiation (LTP) and contextual fear memory were not affected by p110γ overexpression.These results, together with the previous knockout study, suggest that a critical level of PI3Kγ in the hippocampus is required for successful induction of LTD and normal learning.

View Article: PubMed Central - PubMed

ABSTRACT
Previous studies have shown that a family of phosphoinositide 3-kinases (PI3Ks) plays pivotal roles in the brain; in particular, we previously reported that knockout of the γ isoform of PI3K (PI3Kγ) in mice impaired synaptic plasticity and reduced behavioral flexibility. To further examine the role of PI3Kγ in synaptic plasticity and hippocampus-dependent behavioral tasks we overexpressed p110γ, the catalytic subunit of PI3Kγ, in the hippocampal CA1 region. We found that the overexpression of p110γ impairs NMDA receptor-dependent long-term depression (LTD) and hippocampus-dependent spatial learning in the Morris water maze (MWM) task. In contrast, long-term potentiation (LTP) and contextual fear memory were not affected by p110γ overexpression. These results, together with the previous knockout study, suggest that a critical level of PI3Kγ in the hippocampus is required for successful induction of LTD and normal learning.

Show MeSH
Related in: MedlinePlus