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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 normal long-term potentiation (LTP) but exhibit a deficit in long-term depression (LTD).(a) Schematic of recording configuration in hippocampal slices for LTP in the medial perforant path (mPP) of the dentate gyrus. Basal synaptic transmission from wild-type (WT) and Rbfox3−/− (KO) mice was recorded as shown (a) with varying stimulus intensities (0-20 V) plotted against (b), the presynaptic fiber volley amplitudes and (c), the slope of the field excitatory post-synaptic potential (fEPSP) (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (d) Fiber volley amplitude plotted against the slope of fEPSP. (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. Representative traces with varying stimulus intensities from WT and KO mice are shown in (a). Scale bars represent 0.5 mV and 20 ms. (e) Analysis of paired-pulse ratio (PPR) at different interpulse intervals. Representative traces from WT and KO mice are from 50 ms inter-pulse intervals. Scale bars represent 0.25 mV and 10 ms (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (f) Representative waveforms and averaged data of LTP induced with theta burst stimulation (TBS). Bar graph shows comparable LTP in WT and KO mice (WT, n = 10 slices, 5 mice; KO, n = 10 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. (g) Representative waveforms and averaged data of LTD following low frequency stimulation (LFS). Bar graph shows lower LTD for KO than for WT mice. (WT, n = 14 slices, 5 mice; KO, n = 14 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; Student’s t-test, two tailed, *P < 0.05. All data are the mean ± s.e.m.
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f4: Granule cells of adult Rbfox3−/− mice exhibit normal long-term potentiation (LTP) but exhibit a deficit in long-term depression (LTD).(a) Schematic of recording configuration in hippocampal slices for LTP in the medial perforant path (mPP) of the dentate gyrus. Basal synaptic transmission from wild-type (WT) and Rbfox3−/− (KO) mice was recorded as shown (a) with varying stimulus intensities (0-20 V) plotted against (b), the presynaptic fiber volley amplitudes and (c), the slope of the field excitatory post-synaptic potential (fEPSP) (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (d) Fiber volley amplitude plotted against the slope of fEPSP. (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. Representative traces with varying stimulus intensities from WT and KO mice are shown in (a). Scale bars represent 0.5 mV and 20 ms. (e) Analysis of paired-pulse ratio (PPR) at different interpulse intervals. Representative traces from WT and KO mice are from 50 ms inter-pulse intervals. Scale bars represent 0.25 mV and 10 ms (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (f) Representative waveforms and averaged data of LTP induced with theta burst stimulation (TBS). Bar graph shows comparable LTP in WT and KO mice (WT, n = 10 slices, 5 mice; KO, n = 10 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. (g) Representative waveforms and averaged data of LTD following low frequency stimulation (LFS). Bar graph shows lower LTD for KO than for WT mice. (WT, n = 14 slices, 5 mice; KO, n = 14 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; Student’s t-test, two tailed, *P < 0.05. All data are the mean ± s.e.m.

Mentions: Hippocampal long-term potentiation (LTP) and long-term depression (LTD) have been proposed as the primary cellular substrates for fulfilling cognitive functions2930. Moreover, hippocampal LTD mediates spatial reversal learning3132, and hippocampal LTP affects acquisition of spatial learning in the Morris water maze test33. We first examined basal synaptic transmission and synaptic plasticity in the medial perforant path inputs to the dentate gyrus (Fig. 4a). We compared stimulus intensities against the presynaptic fiber volley amplitudes and postsynaptic field excitatory postsynaptic potential (fEPSP) slopes (Fig. 4b–d) and determined Rbfox3−/− mice showed normal presynaptic fiber volley amplitudes but increased fEPSP slopes. This suggested that Rbfox3−/− mice could have more presynaptic release. Indeed, the paired-pulse ratio was reduced in Rbfox3−/− mice (Fig. 4e), which likely indicates that synaptic transmitter release probability is increased343536. Finally, the LTP and LTD of the medial perforant path in the Rbfox3−/− DG were also examined. LTP induced by theta burst stimulation (TBS) was normal in the DG of Rbfox3−/− mice (Fig. 4f), but LTD induced by low frequency stimulation (LFS) was significantly reduced (Fig. 4g). It is interesting to note that LTD deficits are also observed in the hippocampal CA1 region of Rbfox3−/− mice (see Supplementary Fig. S6 online), suggesting the defects in Rbfox3−/− mice are not limited to the DG. Together these results indicate dysfunctional presynaptic releases occur in Rbfox3−/− mice and deficits of LTD but not LTP 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 normal long-term potentiation (LTP) but exhibit a deficit in long-term depression (LTD).(a) Schematic of recording configuration in hippocampal slices for LTP in the medial perforant path (mPP) of the dentate gyrus. Basal synaptic transmission from wild-type (WT) and Rbfox3−/− (KO) mice was recorded as shown (a) with varying stimulus intensities (0-20 V) plotted against (b), the presynaptic fiber volley amplitudes and (c), the slope of the field excitatory post-synaptic potential (fEPSP) (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (d) Fiber volley amplitude plotted against the slope of fEPSP. (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. Representative traces with varying stimulus intensities from WT and KO mice are shown in (a). Scale bars represent 0.5 mV and 20 ms. (e) Analysis of paired-pulse ratio (PPR) at different interpulse intervals. Representative traces from WT and KO mice are from 50 ms inter-pulse intervals. Scale bars represent 0.25 mV and 10 ms (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (f) Representative waveforms and averaged data of LTP induced with theta burst stimulation (TBS). Bar graph shows comparable LTP in WT and KO mice (WT, n = 10 slices, 5 mice; KO, n = 10 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. (g) Representative waveforms and averaged data of LTD following low frequency stimulation (LFS). Bar graph shows lower LTD for KO than for WT mice. (WT, n = 14 slices, 5 mice; KO, n = 14 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; Student’s t-test, two tailed, *P < 0.05. All data are the mean ± s.e.m.
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f4: Granule cells of adult Rbfox3−/− mice exhibit normal long-term potentiation (LTP) but exhibit a deficit in long-term depression (LTD).(a) Schematic of recording configuration in hippocampal slices for LTP in the medial perforant path (mPP) of the dentate gyrus. Basal synaptic transmission from wild-type (WT) and Rbfox3−/− (KO) mice was recorded as shown (a) with varying stimulus intensities (0-20 V) plotted against (b), the presynaptic fiber volley amplitudes and (c), the slope of the field excitatory post-synaptic potential (fEPSP) (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (d) Fiber volley amplitude plotted against the slope of fEPSP. (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. Representative traces with varying stimulus intensities from WT and KO mice are shown in (a). Scale bars represent 0.5 mV and 20 ms. (e) Analysis of paired-pulse ratio (PPR) at different interpulse intervals. Representative traces from WT and KO mice are from 50 ms inter-pulse intervals. Scale bars represent 0.25 mV and 10 ms (WT, n = 7 slices, 3 mice; KO, n = 7 slices, 3 mice). Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05. (f) Representative waveforms and averaged data of LTP induced with theta burst stimulation (TBS). Bar graph shows comparable LTP in WT and KO mice (WT, n = 10 slices, 5 mice; KO, n = 10 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. (g) Representative waveforms and averaged data of LTD following low frequency stimulation (LFS). Bar graph shows lower LTD for KO than for WT mice. (WT, n = 14 slices, 5 mice; KO, n = 14 slices, 5 mice). Scale bars represent 10 ms and 0.5 mV. Two-way repeated measures ANOVA with Holm-Sidak post hoc comparison, *P < 0.05; Student’s t-test, two tailed, *P < 0.05. All data are the mean ± s.e.m.
Mentions: Hippocampal long-term potentiation (LTP) and long-term depression (LTD) have been proposed as the primary cellular substrates for fulfilling cognitive functions2930. Moreover, hippocampal LTD mediates spatial reversal learning3132, and hippocampal LTP affects acquisition of spatial learning in the Morris water maze test33. We first examined basal synaptic transmission and synaptic plasticity in the medial perforant path inputs to the dentate gyrus (Fig. 4a). We compared stimulus intensities against the presynaptic fiber volley amplitudes and postsynaptic field excitatory postsynaptic potential (fEPSP) slopes (Fig. 4b–d) and determined Rbfox3−/− mice showed normal presynaptic fiber volley amplitudes but increased fEPSP slopes. This suggested that Rbfox3−/− mice could have more presynaptic release. Indeed, the paired-pulse ratio was reduced in Rbfox3−/− mice (Fig. 4e), which likely indicates that synaptic transmitter release probability is increased343536. Finally, the LTP and LTD of the medial perforant path in the Rbfox3−/− DG were also examined. LTP induced by theta burst stimulation (TBS) was normal in the DG of Rbfox3−/− mice (Fig. 4f), but LTD induced by low frequency stimulation (LFS) was significantly reduced (Fig. 4g). It is interesting to note that LTD deficits are also observed in the hippocampal CA1 region of Rbfox3−/− mice (see Supplementary Fig. S6 online), suggesting the defects in Rbfox3−/− mice are not limited to the DG. Together these results indicate dysfunctional presynaptic releases occur in Rbfox3−/− mice and deficits of LTD but not LTP 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