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. 2020 Jun 1;123(6):2449-2464.
doi: 10.1152/jn.00523.2019. Epub 2020 May 13.

BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons

Roman U Goz  1   2 , Gülcan Akgül  1 , Joseph J LoTurco  1
Affiliations

BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons

Roman U Goz et al. J Neurophysiol. .

Erratum in

  • CORRIGENDUM.
    [No authors listed] [No authors listed] J Neurophysiol. 2020 Sep 1;124(3):1005. doi: 10.1152/z9k-5591-corr.2020. J Neurophysiol. 2020. PMID: 32924791 Free PMC article. No abstract available.

Abstract

Somatic mutations have emerged as the likely cause of focal epilepsies associated with developmental malformations and epilepsy-associated glioneuronal tumors (GNT). Somatic BRAFV600E mutations in particular have been detected in the majority of low-grade neuroepithelial tumors (LNETS) and in neurons in focal cortical dysplasias adjacent to epilepsy-associated tumors. Furthermore, conditional expression of an activating BRAF mutation in neocortex causes seizures in mice. In this study we characterized the cellular electrophysiology of layer 2/3 neocortical pyramidal neurons induced to express BRAFV600E from neural progenitor stages. In utero electroporation of a piggyBac transposase plasmid system was used to introduce transgenes expressing BRAF wild type (BRAFwt), BRAFV600E, and/or enhanced green fluorescent protein (eGFP) and monomeric red fluorescent protein (mRFP) into radial glia progenitors in mouse embryonic cortex. Whole cell patch-clamp recordings of pyramidal neurons in slices prepared from both juvenile and adult mice showed that BRAFV600E resulted in neurons with a distinct hyperexcitable phenotype characterized by depolarized resting membrane potentials, increased input resistances, lowered action potential (AP) thresholds, and increased AP firing frequencies. Some of the BRAFV600E-expressing neurons normally destined for upper cortical layers by their birthdate were stalled in their migration and occupied lower cortical layers. BRAFV600E-expressing neurons also displayed increased hyperpolarization-induced inward currents (Ih) and decreased sustained potassium currents. Neurons adjacent to BRAFV600E transgene-expressing neurons, and neurons with TSC1 genetically deleted by CRISPR or those induced to carry PIK3CAE545K transgenes, did not show an excitability phenotype similar to that of BRAFV600E-expressing neurons. Together, these results indicate that BRAFV600E leads to a distinct hyperexcitable neuronal phenotype.NEW & NOTEWORTHY This study is the first to report the cell autonomous effects of BRAFV600E mutations on the intrinsic neuronal excitability. We show that BRAFV600E alters multiple electrophysiological parameters in neocortical neurons. Similar excitability changes did not occur in cells neighboring BRAFV600E-expressing neurons, after overexpression of wild-type BRAF transgenes, or after introduction of mutations affecting the mammalian target of rapamycin (mTOR) or the catalytic subunit of phosphoinositide 3-kinase (PIK3CA). We conclude that BRAFV600E causes a distinct, cell autonomous, highly excitable neuronal phenotype when introduced somatically into neocortical neuronal progenitors.

Keywords: BRAFV600E; cortical dysplasia; epilepsy; ganglioglioma; hyperexcitability.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Fig. 1.
Fig. 1.
BRAFV600E-expressing pyramidal neurons are hyperexcitable. A: representative traces of voltage recordings from 4 pyramidal neurons in parietal somatosensory cortex in 4 different conditions. Each neuron is shown responding to 300-pA depolarizing current injection and −40-pA, 1-s hyperpolarizing current injection. Representative traces show the representative phenotypic differences between neurons expressing monomeric red fluorescent protein (mRFP) and/or enhanced green fluorescent protein (eGFP) alone (blue), untransfected cells neighboring BRAFV600E-transfected cells (neighbor; black), a cell expressing wild-type BRAF (BRAFwt; magenta), and BRAFV600E-transfected neurons (red). B: instantaneous frequency (ISF) of action potentials (APs) in the train at +300-pA, 1-s depolarizing current steps was significantly higher in GLAST-prog. BRAFV600E-transfected neurons compared with all other conditions. One-way ANOVA (F6,93–104 = 7.7–28.06, P = 1.0122E-19 to 0.045424; see Supplemental Table S1 at http://doi.org/10.17605/OSF.IO/NRWT2 for more extended statistical comparisons) with Tukey post hoc correction, Welch’s test with Games–Howell post hoc correction, or independent-samples equal variance 2-tailed t tests were used. For instance, the ISF was significantly higher in GLAST-prog. (n = 64) and NESTIN-prog. (n = 8) BRAFV600E neurons compared with untransfected neighbors (n = 7) for the first 3 action potentials in the train (Welch’s test: t6,16.779–18.594 = 14.113–33.123, P = 5E-06 to 2.11E-08 with Games–Howell post hoc correction, P = 1E-06 to 2.01E-07). C: input-output curve shows more than 2 times higher AP firing frequency in GLAST-prog. BRAFV600E-transfected neurons (n = 48) and NESTIN-prog. BRAFV600E transfected neurons (n = 7) compared with all other conditions: GLAST-prog. untransfected neighbor (n = 8), GLAST-prog. eGFP/mRFP (n = 11), GLAST-prog. BRAFwt (n = 13), NESTIN-prog. eGFP/mRFP (n = 3), and NESTIN-prog. untransfected neighbor (n = 6). One-way ANOVA (F6,89 = 33.064–40.874, P = 9.49E-24 to 4.94E-02) with Tukey post hoc correction was used (see Supplemental Table S1 for more extended statistical comparisons). D: sag ratio (SAG) to hyperpolarization is significantly larger in BRAFV600E neurons (n = 57). One-way ANOVA with Tukey’s post hoc tests (F6,108 = 11.46, P = 6.93E-10) was used. **P < 0.01; ***P < 0.001, Tukey post hoc tests (see Supplemental Table S1 for more extended statistical comparisons). E: rebound excitation was significantly larger in BRAFV600E neurons (n = 42). Welch’s test (t6,18.867 = 18.345, P = 6.01E-7) was used to test for significance overall with Games–Howell post hoc correction, and independent-samples 2-tailed t tests were used for statistical comparisons between groups with small sample size. *P < 0.05; **P < 0.01; ***P < 0.001, Tukey or Games–Howell post hoc tests or independent-samples 2-tailed t test. Extended statistical information and comparisons are provided in Supplemental Table S1. AP#, no. of action potentials; AP N, action potential firing frequency; DVmin, minimal initial voltage deflection; DVss, change in stable-state voltage; untr., untransfected.
Fig. 2.
Fig. 2.
Most BRAFV600E neurons migrate to appropriate superficial cortical layers, express pyramidal neuron makers, and do not express interneuron markers. A: images of representative somatosensory cortices containing cells transfected with BRAFV600E, wild-type BRAF (BRAFwt), and enhanced green fluorescent protein (eGFP) transgenes (control-FP). Cux1, an upper cortical layer marker, is expressed by cells in all transfected conditions in superficial cells and in cells ectopically located in deeper layers (bottom row), while Ctip2, a deeper layer marker, is not expressed. Scale bars for A: 500 µm, 50 µm, and 10 µm. B: total neuron counts plotted by their distance from pia (left) and as a percentage of total neurons from the pia (right) indicate a significant proportion of BRAFV600E transgene-containing neurons become positioned abnormally in deeper cortical layers relative to control transfections and BRAFwt. Both GLAST-prog. and NESTIN-prog. progenitor-generated neurons are positioned at a greater distance from the pia than eGFP- or BRAFwt-expressing neurons (Welch’s test: t3,9803.913 = 970.974, P = 0.00E+00). There was also a significant difference in neuronal distance to pia between GLAST and NESTIN transgene conditions such that the population of neurons places in the NESTIN transgene condition (purple lines and bars) were positioned deeper in the cortical lamina, more distant from pia, than the displaced GLAST population (red lines and bars). Extended statistical information and comparisons are provided in Supplemental Table S1 (see http://doi.org/10.17605/OSF.IO/NRWT2). C: images of td-Tomato-labeled interneurons and eGFP-transfected neurons in PV-Cre:Ai14 and SST-Cre:Ai14 mouse lines with BRAFV600E neurons labeled with eGFP. Note that none of the eGFP-positive neurons are positive for either parvalbumin (PV) or somatostatin (SST) reporters. No td-Tomato signal was observed in any of 120 BRAFV600E-transfected neurons in PV-Cre:Ai14xCD1 tissue and none in 42 BRAFV600E-transfected neurons in SST-Cre:Ai14xCD1 tissue.
Fig. 3.
Fig. 3.
Action potential and membrane properties are significantly altered by BRAFV600E. A: the minimal depolarizing current required to induce an action potential (rheobase) is decreased by BRAFV600E. Both NESTIN progenitor (dark purple symbols)- and GLAST progenitor (red symbols)-induced BRAFV600E transgenes caused decreased rheobase in neurons. Due to nonhomogeneous variance, Levene’s test (W6,108 = 4.95, P = 0.000164) and Welch’s test (t6,20.31 = 36.75, P = 7.16E-10) with Games–Howell post hoc correction were used to compare rheobase between experimental conditions. **P < 0.01; ***P < 0.001, Tukey post hoc or independent-samples 2-tailed t test). Extended statistical information and comparisons are provided in Supplemental Table S1 (see http://doi.org/10.17605/OSF.IO/NRWT2). B: voltage threshold for action potentials is decreased by BRAFV600E at the 10 V/s and 50 V/s voltage inflection point. One-way ANOVA for 10V/s (F6,108 = 6.532, P = 7.00E-06) with Tukey post hoc correction was used for statistical comparison. *P < 0.05; **P < 0.01; ***P < 0.001, Tukey post hoc or independent-samples t test. Extended statistical information and comparisons are provided in Supplemental Table S1. C: resting membrane potential (RMP) is elevated in GLAST BRAFV600E and NESTIN BRAFV600E progenitors. One-way ANOVA (F6,121 = 8.51, P = 1.03E-07) with Tukey post hoc correction test was used for statistical comparison. **P < 0.01; ***P < 0.001, Tukey post hoc or independent-samples 2-tailed t test. Extended statistical information and comparisons are provided in Supplemental Table S1. D: AP amplitude measured from RMP was smaller in BRAFV600E neurons (n = 59) relative to untransfected neighboring neurons (n = 14) or to BRAFwt-expressing neurons (n = 18). One-way ANOVA (F6,119 = 5.64, P = 3.50E-05) was used. *P < 0.05;**P < 0.01; ***P < 0.001, Tukey post hoc or independent-samples 2-tailed t test. Extended statistical information and comparisons are provided in Supplemental Table S1. E: input resistance (Rin) was elevated in BRAFV600E neurons (red and purple symbols). Due to nonhomogeneous variance, Levene’s test (W6,97 = 6.49, P = 0.000009) and Welch’s test (t6,23.20 = 8.999, P = 3.90E-05) with Games–Howell post hoc correction were used for input resistance comparisons. *P < 0.05; **P < 0.01; ***P < 0.001, Games–Howell post hoc or independent-samples 2-tailed t test. Error bars are ±2 SE. Extended statistical information and comparisons are provided in Supplemental Table S1. depol., Depolarization; eGFP, enhanced green fluorescent protein; mRFP, monomeric red fluorescent protein; prog., progenitor; untr., untransfected.
Fig. 4.
Fig. 4.
Sustained potassium currents are decreased in GLAST-prog. BRAFV600E neurons compared with their untransfected neighbors. A, left: representative traces of potassium currents in GLAST-prog. BRAFV600E neuron recorded in the presence of 3 mM 4-aminopyridine, 1 µM TTX, 10 µM 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX), 50 µM d-aminophosphonovaleric acid, 10 µM SR-95531, 50 µM ZD-7288, and 1 mM Co2+ substitution for Ca2+ (5 min in, holding voltage is −80 mV, holding current −32.41 pA) with whole cell capacitance compensated (top; ACSF with inhibitor cocktail without TEA; red), where gray bar indicates the region where the measurement was made in all conditions; middle shows traces of the same neuron 9 min after application of 25 mM tetraethylammonium chloride (TEA; green) with previous inhibitor cocktail (holding current −40.25 pA); bottom shows subtracted traces before and after 25 mM TEA with voltage-step protocol (subtracted; cyan). Right: representative traces of potassium currents in GLAST-prog. untransfected neighbors recorded in the presence of the same inhibitor cocktail as at left (6 min in, holding voltage is −80 mV, holding current is −48.04 pA) with whole cell capacitance compensated (top); middle shows traces from the same neuron 9 min after application of 25 mM TEA with previous inhibitor cocktail (holding current −71.67 pA); bottom shows subtracted traces before and after 25 mM TEA. B: average sustained potassium current (IK) activation curve showing decreased peak at all tested voltages in BRAFV600E neurons relative to untransfected neighbors. C: activation curves for the delayed sustained outward currents did not differ for BRAFV600E and untransfected neighboring neurons. D: comparison of maximal sustained outward currents measured at +20-mV voltage step show significant decreases compared with their untransfected neighbors, while the TEA subtracted currents do not show a significant decrease. *P < 0.05; **P < 0.01, either paired-samples or independent-samples 2-tailed t test. Extended statistical information and comparisons are provided in Supplemental Table S1 (see http://doi.org/10.17605/OSF.IO/NRWT2). E: current density was not significantly different between BRAFV600E neurons (n = 18) and untransfected neighbors (n = 7; t23 = 0.509, P = 0.615643). Extended statistical information and comparisons are provided in Supplemental Table S1. F: correlation plots of capacitance (Cm) with sustained potassium currents measured before and after application of 25 mM TEA show no significant correlation of the two values in any of the transfection conditions. R2 adjusted for the variance in each group (reflect R2 divided by degrees of freedom). One-way ANOVA for residuals of the adjusted R2 (R2adj.) for GLAST-prog. BRAFV600E: F = 3.21, P = 0.09; for GLAST-prog. BRAFV600E after 25 mM TEA: F = 1.8, P = 0.24; for GLAST-prog. BRAFV600E subtracted: F = 1.22, P = 0.32; for GLAST-prog. untransfected neighbor: F = 0.03, P = 0.86; for GLAST-prog. untransfected neighbor after 25 mM TEA: F = 8.58, P = 0.1; for GLAST-prog. untransfected neighbor subtracted: F = 0.36, P = 0.61. Extended statistical information and comparisons are provided in Supplemental Table S1. ACSF, artificial cerebrospinal fluid.
Fig. 5.
Fig. 5.
Hyperpolarization-activated depolarizing current (Ih) recorded in whole cell voltage-clamp configuration is increased in BRAFV600E-expressing cortical neurons. A: representative traces of currents in response to hyperpolarizing voltage-step protocol. B: Ih activation curve from the voltage-step protocol shown in A (tail currents, dashed circle) with maximal activation around −120 mV, half-activation voltage (V1/2) of −82.79 mV, and slope factor k of 11.58−1 mV, which are averaged and fit with Boltzmann curve (n = 18). C: representative traces from a single cell in whole cell voltage-clamp configuration. Application of 50 µM ZD-7288, a known Ih inhibitor, in perfusion system for 5 min blocked Ih. D: Ih peak current measured as shown in A. The significant increase was only found in GLAST-prog. BRAFV600E neurons (n = 17) compared with their untransfected neighbors (n = 6; t = 2.117, P = 0.046). E: Ih peak current density was increased in GLAST-prog. BRAFV600E neurons (n = 16) compared with their untransfected neighbors (n = 6; t20 = 3.918, P = 0.000852) and NESTIN-prog. eGFP/mRFP (n = 4; t14.08 = 5.546, P = 0.000071); it was also significantly increased in NESTIN-prog. BRAFV600E neurons (n = 4) compared with GLAST-prog. untransfected neighbors (n = 6; t8 = 3.275, P = 0.011276) and NESTIN-prog. ; enhanced green fluorescent protein/monomeric red fluorescent protein (eGFP/mRFP; n = 4; t4.16 = 3.066, P = 0.035546). *P < 0.05; **P < 0.01; ***P < 0.001, independent-samples 2-tailed t test. Extended statistical information and comparisons are provided in Supplemental Table S1 (see http://doi.org/10.17605/OSF.IO/NRWT2). Error bars are ±2 SE. ACSF, artificial cerebrospinal fluid; Vm, membrane potential.
Fig. 6.
Fig. 6.
Mammalian target of rapamycin (mTOR) pathway mutations result in different pyramidal neuron phenotypes than BRAFV600E. A: representative traces from BRAFV600E (red), PIK3CAE545K (blue), CRISPR knockdown (KD) of TSC1 (brown), and control fluorescent protein-transfected neurons (eGFP/mRFP, enhanced green fluorescent protein/monomeric red fluorescent protein; light purple) showing action potential (AP) firing at +300 pA (upper panel), and response to membrane hyperpolarization by −40 pA. B: average AP firing frequency in all 3 conditions, GLAST-prog. BRAFV600E (n = 49), CRISPR TSC1 KD (n = 11), and GLAST-prog. PIK3CAE545K (n = 11) and in GLAST-prog. eGFP/mRFP (n = 16) and GLAST-prog. PIK3CA E545K untransfected neighbors (n = 4). C: rheobase for all 3 conditions was compared using Welch’s test (t5,17.44 = 36.896, P = 1.11E-08) due to nonhomogeneous variance (Levene’s test: W5,96 = 7.68, P = 4E-06) together with Games–Howell post hoc correction. Rheobase was lower in GLAST-prog. BRAFV600E (n = 49) compared with CRISPR TSC1 KD (n = 11, independent-samples unequal variance 2-tailed t = 11.89, P = 8.3037E-08), GLAST-prog. PIK3CAE545K (n = 11, independent-samples unequal variance 2-tailed t = 3.68, P = 0.004157), and GLAST-prog. eGFP/mRFP (n = 16, independent-samples unequal variance 2-tailed t = 5.95, P = 0.000017). It was significantly higher in CRISPR TSC1 KD (n = 11) compared with GLAST-prog. eGFP/mRFP (n = 16, independent-samples equal variance 2-tailed t = 3.34, P = 0.002604); it was also higher in CRISPR TSC1 KD (n = 11) compared with GLAST-prog. PIK3CA neighbor (n = 3, independent-samples equal variance 2-tailed t = 3.24, P = 0.006437). Extended statistical information and comparisons are provided in Supplemental Table S1 (see http://doi.org/10.17605/OSF.IO/NRWT2). D: AP 50 V/s threshold was not different when compared using Welch’s test (t5,15.16 = 7.551, P = 0.000976) together with Games–Howell post hoc correction due to nonhomogeneous variance (Levene’s test: W5,100 = 7.003, P = 0.000012): GLAST-prog. BRAFV600E (n = 54) compared with CRISPR TSC1 KD (n = 11, independent-samples equal variance 2-tailed t63 = 0.749, P = 0.456642), GLAST-prog. BRAFV600E compared with GLAST-prog. PIK3CAE545K (n = 11, P = 0.12; independent-samples 2-tailed unequal variance Student’s t12.088 = 2.17, P = 0.050665). It was lower in CRISPR TSC1 (n = 11) compared with GLAST-prog. eGFP/mRFP (n = 16, independent-samples equal variance 2-tailed Student’s t25 = 2.871, P = 0.008222). It was significantly lower in GLAST-prog. BRAFV600E (n = 54) compared with GLAST-prog. eGFP/mRFP (n = 16, independent-samples equal variance 2-tailed Student’s t68 = 3.9392, P = 0.000195). Extended statistical information and comparisons are provided in Supplemental Table S1. E: resting membrane potential (RMP; recorded before application of current steps) was compared using Student’s t test. GLAST-prog. BRAFV600E (n = 62) had more depolarized RMP compared with CRISPR TSC1 KD (n = 14, independent-samples equal variance 2-tailed t74 = 7.134, P = 5.5272E-10) and with GLAST-prog. PIK3CAE545K (n = 13, independent-samples equal variance 2-tailed t73 = 3.833, P = 0.000266). RMP was significantly more hyperpolarized in CRISPR TSC1 KD (n = 14) compared with GLAST-prog. PIK3CAE545K (n = 13, independent-samples equal variance 2-tailed t25 = 2.487, P = 0.019922). It was significantly more hyperpolarized in CRISPR TSC1 KD (n = 14) compared with GLAST-prog. eGFP/mRFP (n = 16, independent- sample equal variance 2-tailed t28 = 2.763, P = 0.010002). It was significantly more depolarized in GLAST-prog. BRAFV600E (n = 62) compared with GLAST-prog. eGFP/mRFP (n = 16, independent-samples equal variance 2-tailed t76 = 3.56, P = 0.000643). Extended statistical information and comparisons are provided in Supplemental Table S1. F: input resistance (Rin) from depolarizing current (depol. I) steps (due to hyperpolarization-activated depolarizing current activation in BRAFV600E) was compared using Student’s t test. GLAST-prog. BRAFV600E (n = 38) had higher Rin compared with CRISPR TSC1 KD (n = 14, independent-samples unequal variance 2-tailed t48.252 = 12.33, P = 1.6158E-16) and with GLAST-prog. PIK3CAE545K (n = 12, independent-samples equal variance 2-tailed t48 = 4.66, P = 0.000025). Input resistance was higher in GLAST-prog. BRAFV600E cells (n = 38) compared with GLAT-prog. eGFP/mRFP (n = 16, independent-samples equal variance 2-tailed t52 = 5.28, P = 0.000003). CRISPR TSC1 KD (n = 14) had lower input resistance compared with GLAST-prog. PIK3CAE545K (n = 12, independent-samples unequal variance 2-tailed t12.547 = 2.273, P = 0.041326). Input resistance was significantly lower in CRISPR TSC1 KD (n = 14) compared with GLAST-prog. eGFP/mRFP (n = 16, independent-samples unequal variance 2-tailed t18.953 = 3.259, P = 0.004138). *P < 0.05; **P < 0.01; ***P < 0.001. Extended statistical information and comparisons are provided in Supplemental Table S1.
Fig. 7.
Fig. 7.
BRAFV600E causes development of a distinct class of pyramidal neuron physiology. A: unsupervised hierarchical cluster analysis was performed on 20 recorded electrophysiological parameters, showing that most of the BRAFV600E neurons segregate together by electrophysiological parameters recorded. The parameters are action potential (AP) width at 50% height from resting membrane potential (RMP) in ms, AP maximal decay slope in V/s, AP decay time from 100% to 50% height in ms, AP rise time from 10% to 90% height in ms, AP 50 V/s voltage threshold (thr) in mV, AP 10 V/s voltage threshold in mV, rheobase in pA, afterhyperpolarization (AHP) measured at the end of +300-pA, 1-s current step in mV, AP peak relative to RMP in mV, AP maximal rise slope in V/s, average spontaneous postsynaptic current (sPSC) amplitude (Amp) in pA, average sPSC instantaneous frequency (Freq) in Hz, RMP in mV, input resistance (Rin) from hyperpolarizing pulses in MΩ, Rin from depolarizing pulses in MΩ, number of APs (AP N) at rheobase, medium AHP (mAHP) measured relative to AP 10 V/s voltage threshold for rheobase APs in mV, sag ratio (SAG) in %, AP frequency (AP Fr) at +300-pA, 1-s current step in Hz, and rebound excitation measured as an overshoot above RMP (ADP) in mV. B–E: most contributing electrophysiological parameters to the variability in principal component analysis (PCA) shown in 3-dimensional plots. B: SAG is on the z-axis, AP number at +300-pA, 1-s pulse is on the x-axis, and rebound excitation is on the y-axis. C: SAG is on the z-axis, AHP at the end of +300-pA, 1-s pulse is on the x-axis, and rebound excitation is on the y-axis. D: rheobase is on the z-axis, AP maximal rise slope is on the x-axis, and AP 50 V/s voltage threshold is on the y-axis. E: AP number at +300-pA, 1-s pulse is on the z-axis, resting membrane potential (RMP) is on the x-axis, and input resistance from depolarizing current pulses (Rin) is on the y-axis.
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