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Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility.

Lee K, Kobayashi Y, Seo H, Kwak JH, Masuda A, Lim CS, Lee HR, Kang SJ, Park P, Sim SE, Kogo N, Kawasaki H, Kaang BK, Itohara S - Mol Brain (2015)

Bottom Line: Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive.We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant.We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.

View Article: PubMed Central - PubMed

Affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, 2-101, Dongin-dong, Jung-gu, Daegu, 700-842, Korea. irislkm@knu.ac.kr.

ABSTRACT

Background: Guanine nucleotide exchange factors (GEFs) activate small GTPases that are involved in several cellular functions. cAMP-guanine nucleotide exchange factor II (cAMP-GEF II) acts as a target for cAMP independently of protein kinase A (PKA) and functions as a GEF for Rap1 and Rap2. Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive. Here, we investigated how cAMP-GEF II affects synaptic function and animal behavior using cAMP-GEF II knockout mice.

Results: We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant. On the other hand, it produced a significant and clear impairment in NMDA receptor-dependent long-term depression at the Schaffer collateral-CA1 synapses of hippocampus, while microscopic morphology, basal synaptic transmission, and depotentiation were normal. Behavioral testing using the Morris water maze and automated IntelliCage system showed that cAMP-GEF II deficient mice had moderately reduced behavioral flexibility in spatial learning and memory.

Conclusions: We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.

No MeSH data available.


Related in: MedlinePlus

NMDA receptor-mediated long-term depression and depotentiation in wild-type and cAMP-GEF II−/− mice. a, Long-term depression (LTD) induced by low frequency stimulation (1x LFS; 1 Hz for 15 min) was impaired in cAMP-GEF II−/− (KO) mice. b, There was a significant difference in NMDA receptor-LTD between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording (WT = 75.54 ± 4.27 %, 11 slices from eight mice; KO = 90.74 ± 4.5 %, 9 slices from eight mice; unpaired t-test, p < 0.03). c, Depotentiation in wild-type (WT = 131.55 ± 8.3 %, 8 slices from four mice) and cAMP-GEF II−/− mice (KO = 121.69 ± 9.7 %, 8 slices from four mice; arrow, three trains of theta-burst stimulation). d, There was no difference in depotentiation between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording. Abbreviations: fEPSP, field excitatory postsynaptic potential. NS, no significance
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Fig3: NMDA receptor-mediated long-term depression and depotentiation in wild-type and cAMP-GEF II−/− mice. a, Long-term depression (LTD) induced by low frequency stimulation (1x LFS; 1 Hz for 15 min) was impaired in cAMP-GEF II−/− (KO) mice. b, There was a significant difference in NMDA receptor-LTD between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording (WT = 75.54 ± 4.27 %, 11 slices from eight mice; KO = 90.74 ± 4.5 %, 9 slices from eight mice; unpaired t-test, p < 0.03). c, Depotentiation in wild-type (WT = 131.55 ± 8.3 %, 8 slices from four mice) and cAMP-GEF II−/− mice (KO = 121.69 ± 9.7 %, 8 slices from four mice; arrow, three trains of theta-burst stimulation). d, There was no difference in depotentiation between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording. Abbreviations: fEPSP, field excitatory postsynaptic potential. NS, no significance

Mentions: Because cAMP-GEF II activates Rap1 as an alternative target of cAMP, and the NMDAR-Rap1-p38 MAPK pathway is involved in LTD [6, 11], we assessed NMDAR-LTD induced by low-frequency stimulation (LFS, 1 Hz for 15 min) at SC-CA1 synapses [12] of cAMP-GEF II−/− mice. We found that NMDAR-LTD was absent in cAMP-GEF II−/− mice (90.74 ± 4.51 % of baseline, n = 9 slices from eight animals; p < 0.03) compared to wild-type mice (75.45 ± 4.28 % of baseline, n = 11 slices from eight animals) (Fig. 3a, b). cAMP-GEFs can activate Rap2 as well as Rap1 [1, 2]. It has been reported that the Rap2-c-Jun N-terminal kinase (JNK) pathway is responsible for synaptic depotentiation, which is another form of synaptic depression [11]. Therefore, we assessed depotentiation in the hippocampal CA1 area and found that it was normal in SC-CA1 synapses in cAMP-GEF II−/− mice (121.69 ± 9.71 % of baseline, n = 8 slices from four animals) compared to wild-type mice (131.55 ± 8.31 % of baseline, n = 8 slices from four animals) (Fig. 3c, d), suggesting that cAMP-GEF II deficiency did not affect depotentiation through Rap2. Taken together, our findings imply that cAMP-GEF II is important for NMDAR-LTD induction at hippocampal SC-CA1 synapses.Fig. 3


Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility.

Lee K, Kobayashi Y, Seo H, Kwak JH, Masuda A, Lim CS, Lee HR, Kang SJ, Park P, Sim SE, Kogo N, Kawasaki H, Kaang BK, Itohara S - Mol Brain (2015)

NMDA receptor-mediated long-term depression and depotentiation in wild-type and cAMP-GEF II−/− mice. a, Long-term depression (LTD) induced by low frequency stimulation (1x LFS; 1 Hz for 15 min) was impaired in cAMP-GEF II−/− (KO) mice. b, There was a significant difference in NMDA receptor-LTD between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording (WT = 75.54 ± 4.27 %, 11 slices from eight mice; KO = 90.74 ± 4.5 %, 9 slices from eight mice; unpaired t-test, p < 0.03). c, Depotentiation in wild-type (WT = 131.55 ± 8.3 %, 8 slices from four mice) and cAMP-GEF II−/− mice (KO = 121.69 ± 9.7 %, 8 slices from four mice; arrow, three trains of theta-burst stimulation). d, There was no difference in depotentiation between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording. Abbreviations: fEPSP, field excitatory postsynaptic potential. NS, no significance
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Fig3: NMDA receptor-mediated long-term depression and depotentiation in wild-type and cAMP-GEF II−/− mice. a, Long-term depression (LTD) induced by low frequency stimulation (1x LFS; 1 Hz for 15 min) was impaired in cAMP-GEF II−/− (KO) mice. b, There was a significant difference in NMDA receptor-LTD between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording (WT = 75.54 ± 4.27 %, 11 slices from eight mice; KO = 90.74 ± 4.5 %, 9 slices from eight mice; unpaired t-test, p < 0.03). c, Depotentiation in wild-type (WT = 131.55 ± 8.3 %, 8 slices from four mice) and cAMP-GEF II−/− mice (KO = 121.69 ± 9.7 %, 8 slices from four mice; arrow, three trains of theta-burst stimulation). d, There was no difference in depotentiation between wild-type and cAMP-GEF II−/− mice during the last 5 min of recording. Abbreviations: fEPSP, field excitatory postsynaptic potential. NS, no significance
Mentions: Because cAMP-GEF II activates Rap1 as an alternative target of cAMP, and the NMDAR-Rap1-p38 MAPK pathway is involved in LTD [6, 11], we assessed NMDAR-LTD induced by low-frequency stimulation (LFS, 1 Hz for 15 min) at SC-CA1 synapses [12] of cAMP-GEF II−/− mice. We found that NMDAR-LTD was absent in cAMP-GEF II−/− mice (90.74 ± 4.51 % of baseline, n = 9 slices from eight animals; p < 0.03) compared to wild-type mice (75.45 ± 4.28 % of baseline, n = 11 slices from eight animals) (Fig. 3a, b). cAMP-GEFs can activate Rap2 as well as Rap1 [1, 2]. It has been reported that the Rap2-c-Jun N-terminal kinase (JNK) pathway is responsible for synaptic depotentiation, which is another form of synaptic depression [11]. Therefore, we assessed depotentiation in the hippocampal CA1 area and found that it was normal in SC-CA1 synapses in cAMP-GEF II−/− mice (121.69 ± 9.71 % of baseline, n = 8 slices from four animals) compared to wild-type mice (131.55 ± 8.31 % of baseline, n = 8 slices from four animals) (Fig. 3c, d), suggesting that cAMP-GEF II deficiency did not affect depotentiation through Rap2. Taken together, our findings imply that cAMP-GEF II is important for NMDAR-LTD induction at hippocampal SC-CA1 synapses.Fig. 3

Bottom Line: Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive.We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant.We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.

View Article: PubMed Central - PubMed

Affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, 2-101, Dongin-dong, Jung-gu, Daegu, 700-842, Korea. irislkm@knu.ac.kr.

ABSTRACT

Background: Guanine nucleotide exchange factors (GEFs) activate small GTPases that are involved in several cellular functions. cAMP-guanine nucleotide exchange factor II (cAMP-GEF II) acts as a target for cAMP independently of protein kinase A (PKA) and functions as a GEF for Rap1 and Rap2. Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive. Here, we investigated how cAMP-GEF II affects synaptic function and animal behavior using cAMP-GEF II knockout mice.

Results: We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant. On the other hand, it produced a significant and clear impairment in NMDA receptor-dependent long-term depression at the Schaffer collateral-CA1 synapses of hippocampus, while microscopic morphology, basal synaptic transmission, and depotentiation were normal. Behavioral testing using the Morris water maze and automated IntelliCage system showed that cAMP-GEF II deficient mice had moderately reduced behavioral flexibility in spatial learning and memory.

Conclusions: We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression.

No MeSH data available.


Related in: MedlinePlus