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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

Granule cells of adult Rbfox3−/− mice exhibit increased frequency but normal amplitude of excitatory and inhibitory neurotransmission.Schematics of patch clamp recording of granule cells in hippocampal slices for mEPSC (a) and mIPSC (e). Representative traces from recordings of mEPSC (b) and mIPSC (f). Frequency and cumulative probability are shown for mEPSC (c) and mIPSC (g). Amplitude and cumulative probability are shown for mEPSC (d) and mIPSC (h). (mEPSC: WT, n = 19 cells, 4 mice; KO, n = 21 cells, 4 mice; mIPSC: WT, n = 15 cells, 4 mice; KO, n = 15 cells, 4 mice). Student’s t-test, two tailed, ***P < 0.001. All data are presented as mean ± s.e.m. Scale bars represent 10 pA and 10 sec.
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f5: Granule cells of adult Rbfox3−/− mice exhibit increased frequency but normal amplitude of excitatory and inhibitory neurotransmission.Schematics of patch clamp recording of granule cells in hippocampal slices for mEPSC (a) and mIPSC (e). Representative traces from recordings of mEPSC (b) and mIPSC (f). Frequency and cumulative probability are shown for mEPSC (c) and mIPSC (g). Amplitude and cumulative probability are shown for mEPSC (d) and mIPSC (h). (mEPSC: WT, n = 19 cells, 4 mice; KO, n = 21 cells, 4 mice; mIPSC: WT, n = 15 cells, 4 mice; KO, n = 15 cells, 4 mice). Student’s t-test, two tailed, ***P < 0.001. All data are presented as mean ± s.e.m. Scale bars represent 10 pA and 10 sec.

Mentions: The phenotypes of perforant path LTD and paired pulse ratio in the Rbfox3−/− DG suggest changes of synaptic inputs in the dentate granule cells. We therefore recorded miniature excitatory postsynaptic currents (mEPSCs) in the granule cells of the DG to grossly assess whether synaptic inputs were altered by the deletion of Rbfox3 (Fig. 5a,b). Consistent with our paired-pulse ratio results, mEPSC frequency but not amplitude of mEPSCs was increased in adult (P49) Rbfox3−/− mice (Fig. 5c,d). We also examined spontaneous inhibitory synaptic transmission by recording miniature inhibitory postsynaptic currents (mIPSCs) in the granule cells of the DG (Fig. 5e,f). Similar to our recordings of mEPSCs, granule cells of adult (P49) Rbfox3−/− mice exhibited increased frequency but not amplitude of inhibitory neurotransmission (Fig. 5g,h). To determine whether such dysfunctional neurotransmission begins in young mice, we recorded mEPSC and mIPSC in the granule cells of young (P19) Rbfox3−/− mice. Similar to results from the adult mice, we observed an increase in frequency but not amplitude of excitatory and inhibitory neurotransmission in the granule cells of young (P19) Rbfox3−/− mice (see Supplementary Fig. S7 online). Again, to explore if the defects are present in other regions in the hippocampus, we did these same recordings in the CA1 pyramidal neurons and observed an increase in frequency but not amplitude of excitatory neurotransmission in the CA1 pyramidal neurons of adult (P49) Rbfox3−/− mice (see Supplementary Fig. S8 online). Together, our data strongly indicates that dysfunctional presynaptic releases occur in Rbfox3−/− mice.


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)

Granule cells of adult Rbfox3−/− mice exhibit increased frequency but normal amplitude of excitatory and inhibitory neurotransmission.Schematics of patch clamp recording of granule cells in hippocampal slices for mEPSC (a) and mIPSC (e). Representative traces from recordings of mEPSC (b) and mIPSC (f). Frequency and cumulative probability are shown for mEPSC (c) and mIPSC (g). Amplitude and cumulative probability are shown for mEPSC (d) and mIPSC (h). (mEPSC: WT, n = 19 cells, 4 mice; KO, n = 21 cells, 4 mice; mIPSC: WT, n = 15 cells, 4 mice; KO, n = 15 cells, 4 mice). Student’s t-test, two tailed, ***P < 0.001. All data are presented as mean ± s.e.m. Scale bars represent 10 pA and 10 sec.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664964&req=5

f5: Granule cells of adult Rbfox3−/− mice exhibit increased frequency but normal amplitude of excitatory and inhibitory neurotransmission.Schematics of patch clamp recording of granule cells in hippocampal slices for mEPSC (a) and mIPSC (e). Representative traces from recordings of mEPSC (b) and mIPSC (f). Frequency and cumulative probability are shown for mEPSC (c) and mIPSC (g). Amplitude and cumulative probability are shown for mEPSC (d) and mIPSC (h). (mEPSC: WT, n = 19 cells, 4 mice; KO, n = 21 cells, 4 mice; mIPSC: WT, n = 15 cells, 4 mice; KO, n = 15 cells, 4 mice). Student’s t-test, two tailed, ***P < 0.001. All data are presented as mean ± s.e.m. Scale bars represent 10 pA and 10 sec.
Mentions: The phenotypes of perforant path LTD and paired pulse ratio in the Rbfox3−/− DG suggest changes of synaptic inputs in the dentate granule cells. We therefore recorded miniature excitatory postsynaptic currents (mEPSCs) in the granule cells of the DG to grossly assess whether synaptic inputs were altered by the deletion of Rbfox3 (Fig. 5a,b). Consistent with our paired-pulse ratio results, mEPSC frequency but not amplitude of mEPSCs was increased in adult (P49) Rbfox3−/− mice (Fig. 5c,d). We also examined spontaneous inhibitory synaptic transmission by recording miniature inhibitory postsynaptic currents (mIPSCs) in the granule cells of the DG (Fig. 5e,f). Similar to our recordings of mEPSCs, granule cells of adult (P49) Rbfox3−/− mice exhibited increased frequency but not amplitude of inhibitory neurotransmission (Fig. 5g,h). To determine whether such dysfunctional neurotransmission begins in young mice, we recorded mEPSC and mIPSC in the granule cells of young (P19) Rbfox3−/− mice. Similar to results from the adult mice, we observed an increase in frequency but not amplitude of excitatory and inhibitory neurotransmission in the granule cells of young (P19) Rbfox3−/− mice (see Supplementary Fig. S7 online). Again, to explore if the defects are present in other regions in the hippocampus, we did these same recordings in the CA1 pyramidal neurons and observed an increase in frequency but not amplitude of excitatory neurotransmission in the CA1 pyramidal neurons of adult (P49) Rbfox3−/− mice (see Supplementary Fig. S8 online). Together, our data strongly indicates that dysfunctional presynaptic releases occur in Rbfox3−/− mice.

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