Unique membrane properties and enhanced signal processing in human neocortical neurons

Abstract
Introduction
Results
Discussion
Materials and methods
References
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Abstract

The advanced cognitive capabilities of the human brain are often attributed to our recently evolved neocortex. However, it is not known whether the basic building blocks of the human neocortex, the pyramidal neurons, possess unique biophysical properties that might impact on cortical computations. Here we show that layer 2/3 pyramidal neurons from human temporal cortex (HL2/3 PCs) have a specific membrane capacitance (C_m) of ~0.5 µF/cm², half of the commonly accepted 'universal' value (~1 µF/cm²) for biological membranes. This finding was predicted by fitting in vitro voltage transients to theoretical transients then validated by direct measurement of C_m in nucleated patch experiments. Models of 3D reconstructed HL2/3 PCs demonstrated that such low C_m value significantly enhances both synaptic charge-transfer from dendrites to soma and spike propagation along the axon. This is the first demonstration that human cortical neurons have distinctive membrane properties, suggesting important implications for signal processing in human neocortex.

https://doi.org/10.7554/eLife.16553.001

Introduction

Since the beginnings of modern neuroscience the neocortex has attracted special attention because it is considered to play a key role in human cognition. Starting with the seminal work of Santiago Ramón y Cajal (Cajal, 1995) and Camilo Golgi (Golgi, 1906), and continuing with modern anatomical studies (Jacobs et al., 2001; Watson et al., 2006; DeFelipe, 2011), anatomists have been fascinated by its cellular structure. Comparison of human and rodents cortices shows that the human cortex is thicker (in particular layer 2/3 [DeFelipe et al., 2002; Elston et al., 2001]), contains more white matter (Herculano-Houzel et al., 2010), its neurons are larger (Mohan et al., 2015), and its cortical pyramidal cells have more synaptic connections per cell (15,000–30,000 for layer 2/3 pyramidal neurons [DeFelipe, 2011; DeFelipe et al., 2002]). It seems that the human neocortex, and especially its neurons, is anatomically unique. But what about the biophysical properties, e.g. the specific membrane capacitance of human cortical neurons and their cable characteristics? These have been shown to be key in determining information processing in neurons and in the networks they form (Segev and Rall, 1988; Major et al., 1994; Stuart and Spruston, 1998; Magee, 1998; Segev and London, 2000; Poirazi and Mel, 2001; London and Häusser, 2005; Hay et al., 2011; Eyal et al., 2014; Markram et al., 2015).

To probe the biophysical properties of cortical neurons we built detailed 3D cable and compartmental models of L2/3 pyramidal cells from the human temporal cortex (HL2/3 PCs). The models were based on in vitro intracellular physiological and anatomical data from these same cells. To collect this data, fresh cortical tissue was obtained from brain operations at the neurosurgical department in Amsterdam. Details can be found in our previous works (Testa-Silva et al., 2010; Verhoog et al., 2013; Testa-Silva et al., 2014; Mohan et al., 2015), as well as in the work of other groups (Schwartzkroin and Prince, 1978; Szabadics et al., 2006; Köhling and Avoli, 2006). Our models of human neurons also incorporate data on dendritic spines obtained from light-microscope studies in HL2/3 PCs (Benavides-Piccione et al., 2013; DeFelipe et al., 2002; Elston et al., 2001). These are the first-ever detailed models of human neurons. All modeled cells, implemented in NEURON (Carnevale and Hines, 2006), and the corresponding anatomical and physiological data can be found in Source code 1 and in ModelDB (https://senselab.med.yale.edu/ModelDB/showmodel.cshtml?model=195667).

Results

In Figure 1a, fifty brief depolarizing current pulses (200 pA, 2 ms each) were injected into the soma of the HL2/3 PC shown at the right; the resultant averaged voltage transient is depicted by the black trace. That same cell was then reconstructed in 3D and the dendritic spines were added globally as in Rapp et al. (1992), see Materials and methods. The shape, size, membrane area, and distribution of dendritic spines in the HL2/3 model were based on high-resolution 3D confocal images of several stretches of HL2/3 PCs dendrites (See Materials and methods, Figure 4 and more details in Benavides-Piccione et al., 2013). The 3D anatomy plus physiology were combined for reconstructing a detailed model for that cell. Attempts to fit the experimental transient via the model are depicted by the various colored theoretical transients (see Materials and methods), each with its corresponding values for axial resistivity, R_a, specific membrane resistivity, R_m, and capacitance, C_m. The green transient (with R_a = 203 Ωcm, R_m = 38,907 Ωcm² and C_m = 0.45 μF/cm²) best fitted the experimental transient. Attempts to fit the transient with larger values of C_m failed (red and magenta traces). A close fit between model and experimental transients, with identical cable parameters as the best model in Figure 1a, was obtained for a range of (depolarizing and hyperpolarizing) voltage transients recorded experimentally from that same cell (Figure 1b). A similar range of cable parameters was also found for five additional modeled and experimentally characterized HL2/3 pyramidal cells (Figure 1c1–c5). Furthermore, the low value for C_m, around 0.5 μF/cm², was found in all these five additional modeled cells (C_m= 0.47 ± 0.03 μF/cm², mean ± S.D, n = 6). A summary of the results in Figure 1 is provided in Figure 1—figure supplement 1a1–a3.

Figure 1 with 3 supplements see all

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Exceptionally low specific membrane capacitance, *C_m*, for L2/3 human pyramidal cells predicted using detailed neuron models.

(a) Experimental transient voltage response (upper black trace, *Exp.*) to a brief somatic depolarizing current pulse (2 ms, 200 pA). The corresponding 3D reconstructed HL2/3 cell from which this voltage transient was obtained is shown in the inset. Color traces depict theoretical transients resulting from injecting the experimental current into the compartmental model of that cell (see Materials and methods). The corresponding cable parameters (*C_m*, *R_m*, *R_a*) are shown for each theoretical transient. Excellent fit was obtained only with *C_m* value near 0.5 μF/cm² (green trace), which is half the conventional value of around 1 μF/cm², obtained for a variety of neuron types, including cortical neurons of other species. (b) Model parameters with low *C_m* (green traces in a) also match the experimental responses (black) to stimuli of different strength and signs (−200 pA, −100 pA, −50 pA, 50 pA, 100 pA, 200 pA). (c1–c5) Five additional human L2/3 neurons taken from our human neuron database (depth from pia is provided above each cell). (d1–d5) The experimental transient voltage response for the neurons in c1–c5 (black traces), and models fit to the transients (overlapping color traces). In all models, *C_m* ranged between 0.43 μF/cm²and 0.52 μF/cm². Patient history for these six cells is described in Table 2.

https://doi.org/10.7554/eLife.16553.002

To validate that low C_m values are indeed necessary to achieve good fits between the theoretical and the experimental transients, we plotted (Figure 1—figure supplement 1b–d) the root mean square deviation (RMSD) for different combinations of the three passive parameters (C_m, R_m, R_a) that impact the transients. In all cases, the RMSD obtained with C_m = 0.5 µF/cm² is much smaller than the one obtained with the larger C_m value (Figure 1—figure supplement 1b). R_m values are cell-specific (Figure 1—figure supplement 1c), whereas the value of R_ahas a negligible impact on the RMSD (Figure 1—figure supplement 1d). As in (Major et al., 1994) we found that large R_a value improves the fit over the first two milliseconds of the transient (not shown). Indeed, the best way to directly measure R_a is to use two (somatic and dendritic) electrodes, but this was beyond the scope of the present study. The values in Figure 1 for R_a (268.5 ± 30.0 Ωcm, n = 6) should therefore be viewed with some caution. However, we would like to re-emphasize that our prediction of low C_m value in human L2/3 pyramidal neurons holds independently of the R_a value chosen (Figure 1—figure supplement 1b). We further examined whether possible statistical and systematic errors in the data might effect our estimates of C_m, R_m and R_a by performing error analysis as in Roth and Häusser (2001). We found that even with large systematic errors in morphological parameters, the best fit still yields low C_m value in human L2/3 pyramidal neurons (see Table 1).

Table 1

Estimated statistical and systematic errors in the six human L2/3 PCs models shown in Figure 1 as in (Roth and Häusser, 2001). The mean relative statistical error was 6.5% in C_m (range, 4.2-9.2%, n = 5), 8.6% in R_m (range, 4.2-18.8%, n = 5), and 12.8% in R_a (range, 5.3-20.2%, n = 5). In cell #060311, larger errors were found due to several noisy traces. These range of errors in the estimated values of C_m, R_m and R_a, are within the range of values found for the six modeled cells in Figure 1. We also analyzed the case of systematic errors; the errors introduced are shown in Table 3. This leads to, 40% mean relative error in C_m (range, 36.7–58.2%, n = 6), 30.1% in R_m (range, 28.6–34.1%, n = 6), and 53.0% in R_a (range, 47.3–65.4%, n = 6). Thus, even large systematic errors in morphological parameters cannot explain the low C_m (~0.5 µF/cm²) in human L2/3 pyramidal neurons as compared to the typical value ~1 µF/cm² found in other neurons.

https://doi.org/10.7554/eLife.16553.006

	Cell 060303 (Figure 1c2, blue)			Cell 060308 (Figure 1a, green)			Cell 060311 (Figure 1c3, red)
	Best fit	S.D. stat	S.D. sys	Best fit	S.D. stat	S.D. sys	Best fit	S.D. stat	S.D. sys
C_m (μF/cm²)	0.488	0.045	0.183	0.452	0.026	0.196	0.441	0.248	0.257
R_m (kΩ∙cm²)	21.41	1.21	6.57	38.91	1.65	13.29	48.73	22.90	14.96
R_a (Ω∙cm)	281.78	34.12	152.05	203.23	29.31	96.18	261.97	179.3	127.22

	Cell 130303 (Figure 1c1, orange)			Cell 130305 (Figure 1c5, cyan)			Cell 130306 (Figure 1c4, magenta)
	Best fit	S.D. stat	S.D. sys	Best fit	S.D. stat	S.D. sys	Best fit	S.D. stat	S.D. sys
C_m (μF/cm²)	0.430	0.034	0.158	0.497	0.027	0.207	0.520	0.0219	0.236
R_m (kΩ∙cm²)	35.67	7.40	11.62	31.31	1.99	8.96	36.52	2.89	11.51
R_a (Ω∙cm)	274.44	32.24	171.63	292.95	59.04	164.46	290.28	15.41	137.46

The low C_m value ~ 0.5 μF/cm² found in HL2/3 PCs is surprising; it is commonly assumed that C_m is close to 1 μF/cm² (Hodgkin et al., 1952; Cole, 1968), as was modeled by many researchers on rodent neurons (Major et al., 1994; Roth and Häusser, 2001; Nörenberg et al., 2010; Szoboszlay et al., 2016) and directly confirmed for several classes of neurons using patch recordings from nucleated membrane patches (Gentet et al., 2000). For self-consistency, we repeated the same experimental and theoretical protocols as in Figure 1 on L2/3 PCs from the mouse temporal cortex (n = 4). In contrast to human neurons, and in agreement with the existing literature, we found that the best theoretical fit to the experimental transients yields C_m of 1.09 ± 0.36 µF/cm² (Figure 1—figure supplement 2). This value is significantly larger compared to that found in Figure 1 for human L2/3 neurons (students t-test without the assumption of equal variance, p-val = 0.0408, non parametric Mann-Whitney U-test, p-val = 0.0095). It is important to note that the low value of C_m in human neurons is associated with a high R_m, such that the membrane time constant (τ_m = C_m*R_m) is in the range of 10–22 ms (τ_m = 16.5 ± 3.7, n = 6), which is similar to the value found in the mouse L2/3 pyramidal neurons (τ_m = 16.1 ± 1.3, n = 4) and in rat L2/3 pyramidal cells (τ_m = 13.1 ± 1.7, [Sarid et al., 2007]). This implies that the temporal resolution (the synaptic integration time-window) of human and rodents’ pyramidal L2/3 cells is similar.

Could it be that our uniform passive model used in Figure 1 is too simplistic? Perhaps non-uniform distribution of R_m in the dendrites (as was shown in rodent layer 5 PCs [Stuart and Spruston, 1998] and in inhibitory basket cells [Nörenberg et al., 2010]), or active membrane currents such as Ih that are open around the resting membrane potential (Kole et al., 2006; Harnett et al., 2015), affect our estimation for C_m? These two possibilities were examined via simulations. In the first set of simulations R_m was assumed to be spatially non-uniform in the dendrites of the six modeled cells shown in Figure 1. In each case, the cable properties were optimized in order to best fit the experimental transients (see details in the Materials and methods). In all six cases the estimated C_m for the optimal non-uniform case was similar to the value obtained when R_m was uniform (not shown).

In the next set of simulations Ih was added to the model; the density of the Ih current increased with distance from soma as in Kole et al. (2006), see Materials and methods. The cable properties for the six modeled cells shown in Figure 1 were optimized in order to generate the closest fit between model and experimental transients (see details in the Materials and methods). We found that the larger the Ih density, the larger was the estimated C_m value that best fitted the experimental transient (from ~0.45 μF/cm² without Ih, Figure 1—figure supplement 3a1, to ~0.76 μF/cm² when Ih density at the soma was 0.2 mS/cm2, as found in rat L5PC (Kole et al., 2006), Figure 1—figure supplement 3c1). However, the quality of the fit was significantly reduced compared to the passive case particularly at short times (Figure 1—figure supplement 3b2,c2). Indeed, in the first few milliseconds, the voltage transient is dominated by the capacitive membrane current (and not by the ionic currents, e.g., Ih); at these short times, a close match between model and experiments was obtained only with C_m ~ 0.5 μF/cm², even in the presence of Ih (Figure 1—figure supplement 3d1). We therefore conclude that in order to explain the experimental transients in human L2/3 neurons, C_m should be ~0.5 μF/cm².

This puzzling result of low C_m, values in human neurons inspired us to perform a new set of experiments, using nucleated patches from HL2/3 PCs, in order to directly measure C_m, exactly as in Gentet et al. (2000). We obtained an experimental value for C_m of 0.51 ± 0.11 μF/cm² (mean ± S.D, n = 5 neurons, see details on these cells in Table 2), in full agreement with our model prediction (Figure 2). Repeating the same procedure in mouse neurons resulted in a C_m of 0.83 ± 0.34 μF/cm² (n = 7 neurons from 7 mice; Figure 2d), similar to the findings of (Gentet et al., 2000; Szoboszlay et al., 2016) and significantly different from the human C_m values (students t-test following the KS test for normality (Massey, 1951), p-val = 0.0472). Combining the C_m values obtained in both methods, the model fittings (Figure 1) and the nucleated patches (Figure 2) shows the large difference in C_m between human (C_m = 0.49 ± 0.08 μF/cm², n = 11) and mouse (C_m = 0.93 ± 0.36 μF/cm², n = 11). This difference is highly significant (Figure 2d, students t-test following the KS test for normality, p-val = 0.0021, non-parametric Mann-Whitney U-test, p-val = 0.006). Thus, we find that human L2/3 pyramidal neurons have different membrane capacitance compared to that of rodent pyramidal neurons.

Figure 2

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Nucleated-patch measurement of the specific membrane capacitance in HL2/3 neurons directly validated model prediction for the low *C_m* value in these cells.

(a) Differential Interference Contrast (DIC) image of a human L2/3 pyramidal neuron in an acute brain slice of human temporal cortex targeted for whole-cell patch clamp recording. (b) Nucleated soma patch pulled from the neuron in a. (c) Top trace: Current response of the nucleated patch shown in a to a −5 mV hyperpolarizing step (middle trace). Bottom trace: magnification of the green box in the top trace, showing mono-exponential fit (green line) to the capacitive current from which the total membrane capacitance was extracted. This capacitance was then divided by the surface area of the patch, providing the specific membrane capacitance (see Materials and methods). (d) Summary plot of the specific membrane capacitance from human and mouse. Triangles, *C_m* values from the nucleated patches. Circles, *C_m* values obtained from fitting model to experimental transients (as in Figure 1 and Figure 1—figure supplement 2); human (red, n = 11, see details in Table 2), mouse (blue, n = 11). p-val = 0.0021 using students t-test following the KS test for normality.

https://doi.org/10.7554/eLife.16553.007

To examine the impact of the low C_m value found in HL2/3 neurons on signal processing in these cells, we used the detailed compartmental model for the cell shown in Figure 1a, with model parameters that fit the experimental transients (green curve and corresponding cable parameters). By activating excitatory spiny synapses at both the distal tuft and a distal basal dendrite, we first examined in Figure 3a the impact of the low C_m value on the synaptic charge transfer in HL2/3 dendrites. We found that the peak somatic excitatory postsynaptic potential (EPSP) is larger by ~84% (basal synapse) to ~93% (apical synapse) when C_m = 0.45 μF/cm² (red traces) as compared to the case with C_m = 0.9 μF/cm² (blue traces). We also measured the dendritic delay, defined as the time-difference between that of the local peak EPSP to that of the resultant soma EPSP (Agmon-Snir and Segev, 1993). The dendritic delay from the distal tuft and basal synapses was dramatically reduced from 39 ms and 11 ms when C_m = 0.9 μF/cm² to 20 ms and 6.5 ms respectively, when C_m = 0.45 μF/cm² (see complementary Figure 3—figure supplement 1).

Figure 3 with 1 supplement see all

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Functional implications of the low *C_m* value in human L2/3 cortical neurons for signal processing.

(a) The neuron model shown in Figure 1a, receiving an excitatory synaptic input on distal apical dendritic spine (top trace) and on a distal basal dendritic spine (lower traces). The model cell has either *C_m* = 0.45 μF/cm² (red traces) or *C_m* = 0.9 μF/cm² (blue traces), while the other cable parameters (*R_a* = 203 Ωcm, *R_m* = 38,907 Ωcm²) were kept fixed. Excitatory synapses were activated on the head of the modeled dendritic spine (inset, scale bar is 5 μm; see Materials and methods). Note the larger and faster somatic EPSP for the red case. (b) For the cell model shown in a, significantly smaller number of excitatory spinous synapses were required for initiation of a somatic spike when *C_m* = 0.45 μF/cm². Synapses were simultaneously activated and distributed randomly over the dendritic tree (see Materials and methods). (c) Top, schematics of soma and axon of the cell modeled in a., the axon had a diameter of 1 µm. Bottom, the velocity (θ) of the axonal spike, measured at 1 mm from the soma, is significantly increased (by about 65%) with *C_m* = 0.45 μF/cm² (red spike); the amplitude of the propagated axonal spike is also slightly increased in this case.

https://doi.org/10.7554/eLife.16553.008

We next quantified how many excitatory spinous synapses should be simultaneously activated to initiate a somatic Na⁺ spike in our model for HL2/3 PCs (see Materials and methods). We have used excitatory synapses with both AMPAR and NMDAR currents, with peak conductance values of 0.7 nS and 1.4 nS respectively (See Materials and methods). These synapses were randomly distributed over the modeled HL2/3 dendrites and simultaneously activated. With C_m = 0.45 μF/cm², about 100 excitatory synapses were required for generating a somatic spike with 50% probability, whereas about 170 synapses were required with C_m = 0.9 μF/cm². The lower C_m value as found in HL2/3 pyramidal cells both improved synaptic charge transfer from dendrites to soma (larger EPSPs and reduced dendritic delay) and also reduced the number of synapses required to initiate a somatic/axonal spike, thus compensating for the increase in the size of the dendritic tree in human neocortex (Mohan et al., 2015).

We further explored the impact of C_m ~ 0.5 μF/cm² on the velocity of spike propagation along the axon (Figure 3c). We examined the case of a long non-myelinated axon, assuming that C_m in the axon is similar to that of the cell body. As expected, a lower C_m value increased the propagation speed of the action potential; for the parameters we used, the propagation was about 65% faster compared with the case of a higher C_m. This is in agreement with the analytical result obtained by (Jack et al., 1975, page 432) for the impact of C_m on spike propagation velocity. Thus, low C_m value enables an efficient intra- and inter-regional information-transfer despite the large size of the human brain.

Discussion

Our study provides the first direct evidence for the unique properties of the membrane in human cortical cells. In particular, we showed that layer 2/3 pyramidal neurons from human temporal cortex have a specific membrane capacitance (C_m) of ~0.5 µF/cm², half of the commonly accepted ‘universal’ value (~1 µF/cm²) for biological membranes. It is important to note that a few studies have demonstrated that C_m in rodent’s pyramidal neurons may range between 0.7–2 µF/cm² (Major et al., 1994; Thurbon et al., 1998), but direct measurements using nucleated patches found a much narrower range, 0.8–1.1 µF/cm², in cortical pyramidal neurons (Gentet et al., 2000; Szoboszlay et al., 2016), as well as in cerebellar Golgi cells (Szoboszlay et al., 2016). This narrow range of values also agrees with the modeling prediction of (Nörenberg et al., 2010) for GABAergic hippocampal interneurons, where a correction for the spines area is not required. In the present work, we used both a modeling approach, as well as nucleated patch experiments, to demonstrate that C_m in human L2/3 pyramidal neurons is significantly lower than in rodents. We next demonstrated that such low C_m value has important functional implications for signal processing in dendrites and axons.

One may argue that the neurons we used have abnormal membrane properties as these neurons originated from humans with epileptic seizures. However, we only used brain samples that were not part of the diseased tissues, but had to be removed in order to gain access to deeper brain structures for surgical treatment. The eleven HL2/3 pyramidal cells used in this research (six cells in Figure 1 and five cells in Figure 2) were taken from five different human patients with different disease records that were treated with different drugs (see Table 2). Yet, in all cases we found similar membrane properties. Furthermore, we recently have shown that there is no correlation between the disease history (epilepsy onset and total numbers of seizures) and the neuron morphology (Mohan et al., 2015).

Unfortunately, we do not yet have a comprehensive comparative study for assessing the value of C_m in other large brains, e.g., those of non-human primates. Recent compartmental models of pyramidal neurons in L3 of the prefrontal cortex of rhesus monkeys suggested that aged animals have smaller C_m values (~0.7 µF/cm²) than young animals (~1.1 µF/cm²) (Rumbell et al., 2016). Further direct measurements of C_m, e.g., using the nucleated patch technique in different animals, could provide insights to the evolution of the specific capacitance of neuronal membranes.

What could be the reason for the low C_m as found in the present work? The specific capacitance is determined by the dielectric constant of the material composing the membrane and by the membrane thickness. We measured the membrane thickness in a few samples from human and mouse L2/3 pyramidal cells, both from the temporal cortex; both showed similar thickness of 5.1–5.8 nm (not shown). Another possibility that might explain differences in C_m is the compositions of neuronal membranes. Gentet et al. (2000) demonstrated that transmembrane proteins have small effect on C_m. However, a recent study showed that C_m of condensed phosphatidylcholine-based monolayers is sensitive to their lipid composition and molecular arrangement (Lecompte et al., 2015). Furthermore, Szoboszlay et al. (2016), using nucleated patch experiments on mouse cerebellar neurons, showed that C_m increases significantly (from 1 µF/cm² to more than 2 µF/cm²) after adding Mefloquine to the bath; Mefloquine is known to bind to the membrane phospholipids (Chevli and Fitch, 1982). Interestingly, (Bozek et al., 2015) showed a significant difference in the lipidome of human, chimpanzee, macaque, and mouse. More specifically, Moschetta et al. (2005) and Chan et al. (2012) showed differences in the ratio between phospholipids, cholesterol, and sphingomyelin in human vs. rodents. In view of the above studies, we suggest that the lipid composition of HL2/3 membrane explains their low C_m. This assertion requires direct examination of the human membranes at the molecular level, which is beyond the scope of the present study.

Whatever the reason, the low C_m effectively enhances signal transfer (both synaptic and action potentials, Figure 3 and Figure 3—figure supplement 1) and increases the neuron’s excitability, so that less depolarizing charge is required for generating Na⁺ spikes and for supporting dendritic backpropagating Na⁺ action potentials (Stuart and Sakmann, 1994). We conclude by suggesting that the distinctive biophysical membrane properties of pyramidal neurons in human evolved as an outcome of evolutionary pressure and resulted in an efficient information transfer, counteracting the increase in size/distances in the human brain.

Gender	Age (years)	Age at epilepsy onset (years)	Diagnosis	Seizure frequency (per month)	Antiepileptic drugs (pre-surgery)	Data used in figure
Male	25	24	Tumor	8	LEV, CBZ, LCS	Figure 1: a, c2, c3
Female	45	23	MTS (meningitis)	3	CBZ, CLB, LTG	Figure 1: c1, c4, c5
Female	40	16	MTS	7	ZGR, LTG, FRI, MDZ	Figure 2
Male	43	6	MTS	7	LEV, OXC	Figure 2
Male	51	4	unknown etiology	60	CBZ, FRI	Figure 2

Error variable	Estimated S.D.
Scale factor for lengths in the morphological reconstruction	0.05
Additive error in reconstructed diameters (µm)	0.3
Multiplicative error in reconstructed diameters	0.1
Error in spine scale factor, F	0.4
Error in the start point of high density spines (μm)	30

	AMPA	NMDA
$τ_{r i s e} (m s)$	0.3	3
$τ_{d e c a y} (m s)$	1.8	70
$g_{max}$ (nS)	0.7	1.4
$γ$ $(\frac{1}{m V})$	-	0.08
$n$ $(\frac{1}{m M})$	-	1/3.57
$[M g^{2 +}]$	-	1 mM

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Exceptionally low specific membrane capacitance, Cm, for L2/3 human pyramidal cells predicted using detailed neuron models.

Nucleated-patch measurement of the specific membrane capacitance in HL2/3 neurons directly validated model prediction for the low Cm value in these cells.

Functional implications of the low Cm value in human L2/3 cortical neurons for signal processing.

High resolution reconstruction of spines from HL2/3 dendrites.

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Guy Eyal

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Matthijs B Verhoog

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Guilherme Testa-Silva

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Yair Deitcher

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Johannes C Lodder

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Ruth Benavides-Piccione

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Juan Morales

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Javier DeFelipe

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Christiaan PJ de Kock

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Huibert D Mansvelder

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Idan Segev

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For correspondence

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Exceptionally low specific membrane capacitance, C_m, for L2/3 human pyramidal cells predicted using detailed neuron models.

Nucleated-patch measurement of the specific membrane capacitance in HL2/3 neurons directly validated model prediction for the low C_m value in these cells.

Functional implications of the low C_m value in human L2/3 cortical neurons for signal processing.