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RBFOX3/NeuN is Required for Hippocampal Circuit Balance and Function.

Wang HY, Hsieh PF, Huang DF, Chin PS, Chou CH, Tung CC, Chen SY, Lee LJ, Gau SS, Huang HS - Sci Rep (2015)

Bottom Line: RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood.Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway.The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.

ABSTRACT
RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders.

No MeSH data available.


Related in: MedlinePlus

Rbfox3−/− mice exhibit increased seizure susceptibility and decreased anxiety.(a) Seizure scores and death rate for WT and Rbfox3−/− (KO) mice treated with kainic acid. The mortality rate of KO mice was 17.65%. Mann-Whitney rank sum test or Fisher’s exact test, *P < 0.05, #P < 0.1; WT, n = 19, KO, n = 17. Behavior was measured for WT and Rbfox3−/− (KO) mice as follows: (b) Acquisition and reversal of spatial learning scores in the Morris water maze over 9 days of testing. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; WT n = 11, KO, n = 9. (c) Stress-induced anxiety measurements using the novelty suppressed feeding test (WT = W. Rbfox3−/− = K). Student’s t-test, two-tailed, *P < 0.05; W, n = 12, K, n = 8. (d) Abnormal behavior scored by number of marbles buried with the marble-burying test. Mann-Whitney Rank Sum test, *P < 0.05; WT, n = 12, KO, n = 9. (e) Anxiety-like behavior measured with the elevated plus-maze test. Student’s t-test, two-tailed, **P < 0.01, ***P < 0.001; WT/W, n = 12, KO/K, n = 9. (f) An open field analysis of locomotion test also measured anxiety. Student’s t-test, two-tailed, #P < 0.1; WT, n = 12, KO, n = 9.
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f2: Rbfox3−/− mice exhibit increased seizure susceptibility and decreased anxiety.(a) Seizure scores and death rate for WT and Rbfox3−/− (KO) mice treated with kainic acid. The mortality rate of KO mice was 17.65%. Mann-Whitney rank sum test or Fisher’s exact test, *P < 0.05, #P < 0.1; WT, n = 19, KO, n = 17. Behavior was measured for WT and Rbfox3−/− (KO) mice as follows: (b) Acquisition and reversal of spatial learning scores in the Morris water maze over 9 days of testing. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; WT n = 11, KO, n = 9. (c) Stress-induced anxiety measurements using the novelty suppressed feeding test (WT = W. Rbfox3−/− = K). Student’s t-test, two-tailed, *P < 0.05; W, n = 12, K, n = 8. (d) Abnormal behavior scored by number of marbles buried with the marble-burying test. Mann-Whitney Rank Sum test, *P < 0.05; WT, n = 12, KO, n = 9. (e) Anxiety-like behavior measured with the elevated plus-maze test. Student’s t-test, two-tailed, **P < 0.01, ***P < 0.001; WT/W, n = 12, KO/K, n = 9. (f) An open field analysis of locomotion test also measured anxiety. Student’s t-test, two-tailed, #P < 0.1; WT, n = 12, KO, n = 9.

Mentions: To determine if genetic deletion of Rbfox3 in mice could recapitulate features of RBFOX3-linked human neurological disorders, we examined seizure susceptibility, cognitive function and anxiety-related behaviors in Rbfox3−/− mice. Rbfox1 knockout mice have been shown to exhibit a significant epileptic phenotype6. Persons with a deletion of RBFOX3 are susceptible to seizures, suggesting RBFOX3 may play a role in seizure susceptibility. Since hippocampal dentate gyrus receives kainic acid (KA)-sensitive excitatory inputs that can initiate temporal lobe epilepsy21, we first examined the seizure susceptibility of Rbfox3−/− mice after KA treatment, a well-established model of status epilepticus22. Treatment with KA resulted in significantly higher seizure scores and fatality in Rbfox3−/− mice than wild-type mice (Fig. 2a). However, we did not observe spontaneous seizures in Rbfox3−/− mice (n = 5) during one week of continuous observation.


RBFOX3/NeuN is Required for Hippocampal Circuit Balance and Function.

Wang HY, Hsieh PF, Huang DF, Chin PS, Chou CH, Tung CC, Chen SY, Lee LJ, Gau SS, Huang HS - Sci Rep (2015)

Rbfox3−/− mice exhibit increased seizure susceptibility and decreased anxiety.(a) Seizure scores and death rate for WT and Rbfox3−/− (KO) mice treated with kainic acid. The mortality rate of KO mice was 17.65%. Mann-Whitney rank sum test or Fisher’s exact test, *P < 0.05, #P < 0.1; WT, n = 19, KO, n = 17. Behavior was measured for WT and Rbfox3−/− (KO) mice as follows: (b) Acquisition and reversal of spatial learning scores in the Morris water maze over 9 days of testing. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; WT n = 11, KO, n = 9. (c) Stress-induced anxiety measurements using the novelty suppressed feeding test (WT = W. Rbfox3−/− = K). Student’s t-test, two-tailed, *P < 0.05; W, n = 12, K, n = 8. (d) Abnormal behavior scored by number of marbles buried with the marble-burying test. Mann-Whitney Rank Sum test, *P < 0.05; WT, n = 12, KO, n = 9. (e) Anxiety-like behavior measured with the elevated plus-maze test. Student’s t-test, two-tailed, **P < 0.01, ***P < 0.001; WT/W, n = 12, KO/K, n = 9. (f) An open field analysis of locomotion test also measured anxiety. Student’s t-test, two-tailed, #P < 0.1; WT, n = 12, KO, n = 9.
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Related In: Results  -  Collection

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f2: Rbfox3−/− mice exhibit increased seizure susceptibility and decreased anxiety.(a) Seizure scores and death rate for WT and Rbfox3−/− (KO) mice treated with kainic acid. The mortality rate of KO mice was 17.65%. Mann-Whitney rank sum test or Fisher’s exact test, *P < 0.05, #P < 0.1; WT, n = 19, KO, n = 17. Behavior was measured for WT and Rbfox3−/− (KO) mice as follows: (b) Acquisition and reversal of spatial learning scores in the Morris water maze over 9 days of testing. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; WT n = 11, KO, n = 9. (c) Stress-induced anxiety measurements using the novelty suppressed feeding test (WT = W. Rbfox3−/− = K). Student’s t-test, two-tailed, *P < 0.05; W, n = 12, K, n = 8. (d) Abnormal behavior scored by number of marbles buried with the marble-burying test. Mann-Whitney Rank Sum test, *P < 0.05; WT, n = 12, KO, n = 9. (e) Anxiety-like behavior measured with the elevated plus-maze test. Student’s t-test, two-tailed, **P < 0.01, ***P < 0.001; WT/W, n = 12, KO/K, n = 9. (f) An open field analysis of locomotion test also measured anxiety. Student’s t-test, two-tailed, #P < 0.1; WT, n = 12, KO, n = 9.
Mentions: To determine if genetic deletion of Rbfox3 in mice could recapitulate features of RBFOX3-linked human neurological disorders, we examined seizure susceptibility, cognitive function and anxiety-related behaviors in Rbfox3−/− mice. Rbfox1 knockout mice have been shown to exhibit a significant epileptic phenotype6. Persons with a deletion of RBFOX3 are susceptible to seizures, suggesting RBFOX3 may play a role in seizure susceptibility. Since hippocampal dentate gyrus receives kainic acid (KA)-sensitive excitatory inputs that can initiate temporal lobe epilepsy21, we first examined the seizure susceptibility of Rbfox3−/− mice after KA treatment, a well-established model of status epilepticus22. Treatment with KA resulted in significantly higher seizure scores and fatality in Rbfox3−/− mice than wild-type mice (Fig. 2a). However, we did not observe spontaneous seizures in Rbfox3−/− mice (n = 5) during one week of continuous observation.

Bottom Line: RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood.Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway.The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.

ABSTRACT
RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders.

No MeSH data available.


Related in: MedlinePlus