Limits...
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 display normal neuronal intrinsic excitability.(a) Schematic of granule cell recording in a hippocampal slice at P49. (b) Representative response to current injections and average spike frequency-current curves (WT, n = 14 cells, 5 mice; KO, n = 15 cells, 5 mice). Scale bars represent 20 mV and 200 ms. (c) Intrinsic parameters of granule cells were measured. Abbreviations: Rin = input resistance, RMP = resting membrane potential, AP = action potential, mAHP = medium afterhyperpolarization, fAHP = fast afterhyperpolarization. All data are presented as mean ± s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664964&req=5

f3: Granule cells of adult Rbfox3−/− mice display normal neuronal intrinsic excitability.(a) Schematic of granule cell recording in a hippocampal slice at P49. (b) Representative response to current injections and average spike frequency-current curves (WT, n = 14 cells, 5 mice; KO, n = 15 cells, 5 mice). Scale bars represent 20 mV and 200 ms. (c) Intrinsic parameters of granule cells were measured. Abbreviations: Rin = input resistance, RMP = resting membrane potential, AP = action potential, mAHP = medium afterhyperpolarization, fAHP = fast afterhyperpolarization. All data are presented as mean ± s.e.m.

Mentions: Neurons in Rbfox1 deletion mice have been shown to exhibit increased intrinsic excitability6, and our Rbfox3−/− mice showed increased seizure susceptibility (Fig. 2a), suggesting that the DG cells in Rbfox3−/− mice might exhibit abnormal neuronal intrinsic excitability. We therefore examined the neuronal intrinsic excitability of dentate granule cells in Rbfox3−/− mice by injecting varying currents into the cells from adult (P49) Rbfox3−/− and wild-type mice and measuring action potential firing pattern (Fig. 3a). All cells recorded were mature granule cells (input resistance was less than 0.4 GΩ) and surprisingly, all cells displayed normal firing rates and patterns against different injecting currents (Fig. 3b). Moreover, we observed normal input resistance, rheobase, resting membrane potential, and decay of time constant (Fig. 3c). As additional controls, we found normal neuronal intrinsic excitability in dentate granule cells of young (P19) Rbfox3−/− mice (see Supplementary Fig. S4 online) and CA1 pyramidal neurons of adult (P49) Rbfox3−/− mice (see Supplementary Fig. S5 online). These data suggest that, unlike Rbfox1 deletion mice, dentate granule neurons and CA1 pyramidal neurons of Rbfox3−/− mice exhibit normal intrinsic excitability. Interestingly, we did not observe a difference in Rbfox1 expression level in Rbfox3−/− mice compared to their wild-type counterparts (see Supplementary Fig. S3 online). These results imply that the increased seizure susceptibility in Rbfox3−/− mice could be through mechanisms other than those in Rbfox1−/− 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 display normal neuronal intrinsic excitability.(a) Schematic of granule cell recording in a hippocampal slice at P49. (b) Representative response to current injections and average spike frequency-current curves (WT, n = 14 cells, 5 mice; KO, n = 15 cells, 5 mice). Scale bars represent 20 mV and 200 ms. (c) Intrinsic parameters of granule cells were measured. Abbreviations: Rin = input resistance, RMP = resting membrane potential, AP = action potential, mAHP = medium afterhyperpolarization, fAHP = fast afterhyperpolarization. All data are presented as mean ± s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Granule cells of adult Rbfox3−/− mice display normal neuronal intrinsic excitability.(a) Schematic of granule cell recording in a hippocampal slice at P49. (b) Representative response to current injections and average spike frequency-current curves (WT, n = 14 cells, 5 mice; KO, n = 15 cells, 5 mice). Scale bars represent 20 mV and 200 ms. (c) Intrinsic parameters of granule cells were measured. Abbreviations: Rin = input resistance, RMP = resting membrane potential, AP = action potential, mAHP = medium afterhyperpolarization, fAHP = fast afterhyperpolarization. All data are presented as mean ± s.e.m.
Mentions: Neurons in Rbfox1 deletion mice have been shown to exhibit increased intrinsic excitability6, and our Rbfox3−/− mice showed increased seizure susceptibility (Fig. 2a), suggesting that the DG cells in Rbfox3−/− mice might exhibit abnormal neuronal intrinsic excitability. We therefore examined the neuronal intrinsic excitability of dentate granule cells in Rbfox3−/− mice by injecting varying currents into the cells from adult (P49) Rbfox3−/− and wild-type mice and measuring action potential firing pattern (Fig. 3a). All cells recorded were mature granule cells (input resistance was less than 0.4 GΩ) and surprisingly, all cells displayed normal firing rates and patterns against different injecting currents (Fig. 3b). Moreover, we observed normal input resistance, rheobase, resting membrane potential, and decay of time constant (Fig. 3c). As additional controls, we found normal neuronal intrinsic excitability in dentate granule cells of young (P19) Rbfox3−/− mice (see Supplementary Fig. S4 online) and CA1 pyramidal neurons of adult (P49) Rbfox3−/− mice (see Supplementary Fig. S5 online). These data suggest that, unlike Rbfox1 deletion mice, dentate granule neurons and CA1 pyramidal neurons of Rbfox3−/− mice exhibit normal intrinsic excitability. Interestingly, we did not observe a difference in Rbfox1 expression level in Rbfox3−/− mice compared to their wild-type counterparts (see Supplementary Fig. S3 online). These results imply that the increased seizure susceptibility in Rbfox3−/− mice could be through mechanisms other than those in Rbfox1−/− 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