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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

Basal synaptic properties and long-term potentiation in wild-type and cAMP-GEF II−/− mice. a, Input–output curves as a measure of baseline excitatory synaptic transmission showed no difference between the two genotypes (WT = 8 slices from six mice; KO = 8 slices from six mice). b, Long-term potentiation (LTP) induced by high frequency stimulation (arrow, 1x HFS; 100 Hz for 1 s) was slightly impaired without statistical significance in Schaffer collateral-CA1 (SC-CA1) synapses of cAMP-GEF II−/− mice (WT = 171.54 ± 7.61 %, 8 slices from eight mice; KO = 156.74 ± 7.76 %, 8 slices from eight mice; unpaired t-test, p = 0.195). c, Paired pulse facilitation (PPF) ratio did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from six mice). d, Post-tetanic potentiation (PTP) also did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from five mice; arrow, 1x HFS). Abbreviations: fEPSP, field excitatory postsynaptic potential; HFS, high frequency stimulation
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Fig2: Basal synaptic properties and long-term potentiation in wild-type and cAMP-GEF II−/− mice. a, Input–output curves as a measure of baseline excitatory synaptic transmission showed no difference between the two genotypes (WT = 8 slices from six mice; KO = 8 slices from six mice). b, Long-term potentiation (LTP) induced by high frequency stimulation (arrow, 1x HFS; 100 Hz for 1 s) was slightly impaired without statistical significance in Schaffer collateral-CA1 (SC-CA1) synapses of cAMP-GEF II−/− mice (WT = 171.54 ± 7.61 %, 8 slices from eight mice; KO = 156.74 ± 7.76 %, 8 slices from eight mice; unpaired t-test, p = 0.195). c, Paired pulse facilitation (PPF) ratio did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from six mice). d, Post-tetanic potentiation (PTP) also did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from five mice; arrow, 1x HFS). Abbreviations: fEPSP, field excitatory postsynaptic potential; HFS, high frequency stimulation

Mentions: We tested the input–output function in SC-CA1 synapses of hippocampal slices in order to evaluate the effect of the lack of cAMP-GEF II on basal synaptic transmission using extracellular field potential recording. Basal synaptic strength was indistinguishable between the two genotypes (Fig. 2a), indicating that genetic deletion of cAMP-GEF II did not affect basal synaptic transmission. We then examined the physiological role of cAMP-GEF II in hippocampal synaptic plasticity. High frequency stimulation (HFS, 100 Hz for 1 s) of afferent fibers induced LTP in SC-CA1 excitatory synapses in both wild-type and cAMP-GEF II−/− mice (Fig. 2b). However, the magnitude of LTP during the last 10 minutes in cAMP-GEF II−/− mice was moderately smaller than in wild-type mice (WT: 171.54 ± 7.61 % of baseline, n = 8 slices from eight animals; cAMP-GEF II−/−: 156.74 ± 7.76 % of baseline, n = 8 slices from eight animals; p = 0.195) (Fig. 2b), although there was no statistical significance.Fig. 2


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)

Basal synaptic properties and long-term potentiation in wild-type and cAMP-GEF II−/− mice. a, Input–output curves as a measure of baseline excitatory synaptic transmission showed no difference between the two genotypes (WT = 8 slices from six mice; KO = 8 slices from six mice). b, Long-term potentiation (LTP) induced by high frequency stimulation (arrow, 1x HFS; 100 Hz for 1 s) was slightly impaired without statistical significance in Schaffer collateral-CA1 (SC-CA1) synapses of cAMP-GEF II−/− mice (WT = 171.54 ± 7.61 %, 8 slices from eight mice; KO = 156.74 ± 7.76 %, 8 slices from eight mice; unpaired t-test, p = 0.195). c, Paired pulse facilitation (PPF) ratio did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from six mice). d, Post-tetanic potentiation (PTP) also did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from five mice; arrow, 1x HFS). Abbreviations: fEPSP, field excitatory postsynaptic potential; HFS, high frequency stimulation
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Fig2: Basal synaptic properties and long-term potentiation in wild-type and cAMP-GEF II−/− mice. a, Input–output curves as a measure of baseline excitatory synaptic transmission showed no difference between the two genotypes (WT = 8 slices from six mice; KO = 8 slices from six mice). b, Long-term potentiation (LTP) induced by high frequency stimulation (arrow, 1x HFS; 100 Hz for 1 s) was slightly impaired without statistical significance in Schaffer collateral-CA1 (SC-CA1) synapses of cAMP-GEF II−/− mice (WT = 171.54 ± 7.61 %, 8 slices from eight mice; KO = 156.74 ± 7.76 %, 8 slices from eight mice; unpaired t-test, p = 0.195). c, Paired pulse facilitation (PPF) ratio did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from six mice). d, Post-tetanic potentiation (PTP) also did not differ between wild-type and cAMP-GEF II−/− mice (WT = 8 slices from six mice; KO = 8 slices from five mice; arrow, 1x HFS). Abbreviations: fEPSP, field excitatory postsynaptic potential; HFS, high frequency stimulation
Mentions: We tested the input–output function in SC-CA1 synapses of hippocampal slices in order to evaluate the effect of the lack of cAMP-GEF II on basal synaptic transmission using extracellular field potential recording. Basal synaptic strength was indistinguishable between the two genotypes (Fig. 2a), indicating that genetic deletion of cAMP-GEF II did not affect basal synaptic transmission. We then examined the physiological role of cAMP-GEF II in hippocampal synaptic plasticity. High frequency stimulation (HFS, 100 Hz for 1 s) of afferent fibers induced LTP in SC-CA1 excitatory synapses in both wild-type and cAMP-GEF II−/− mice (Fig. 2b). However, the magnitude of LTP during the last 10 minutes in cAMP-GEF II−/− mice was moderately smaller than in wild-type mice (WT: 171.54 ± 7.61 % of baseline, n = 8 slices from eight animals; cAMP-GEF II−/−: 156.74 ± 7.76 % of baseline, n = 8 slices from eight animals; p = 0.195) (Fig. 2b), although there was no statistical significance.Fig. 2

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