星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电

独盟盟，袁治轩，李佳佳，吴莹; Du Mengmeng; Yuan Zhixuan; Li Jiajia; Wu Ying

引 en

星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电^∗

独盟盟¹
，袁治轩¹
，李佳佳¹
，吴莹^1,2

1. 西安交通大学机械结构强度与振动国家重点实验室,航天航空学院,西安 710049； 2. 西安交通大学力学实验教学国家示范中心,西安 710049；

VOlTAGE-GATED CALCIUM CHANNELS IN ASTRCOCYTES REGULATING EPILEPTIC SEIZURES ^∗

Du Mengmeng¹
， Yuan Zhixuan¹
， Li Jiajia¹
， Wu Ying^1,2

1. School of Aerospace Engineering,State Key Laboratory for Strength and Vibration of Mechanical Structures, Xi’an Jiaotong University,Xi’an 710049 China； 2. National Demonstration Center for Experimental Mechanics Education,Xi’an Jiaotong University,Xi’an 710049 China；

文章编号:1672-6553/2020/18⑴/049-07

DOI:10.6052/1672-6553-2020-012

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摘要

细胞外空间钾离子的大量积累会导致星形胶质细胞膜去极化,星形胶质细胞膜电位变化引起的电压门控钙离子通道(VGCCs)电流内流会增加星形胶质细胞内钙离子浓度的振荡幅值,从而增强星形胶质细胞对神经元的正反馈作用.考虑星形胶质细胞 VGCCs 的钙离子内流,本文构建了一种包含多种离子浓度动力学行为的神经元-胶质细胞耦合模型.数值模拟结果发现,VGCCs 的钙离子内流是影响星形胶质细胞内 Ca ²⁺ 浓度升高的一个主要因素，VGCCs 电流增强会诱发神经元产生自发性癫痫放电活动实验现象的内在机理. 本文研究结果可以为星形胶质细胞钙离子代谢紊乱诱发神经系统自发性癫痫放电提供一种解释.

Abstract

The accumulation of extracellular potassium(K ⁺ )concentration induces astrocytes membrane depolari- zation,which causes the voltage-gated calcium channel(VGCCs)current flow into astrocyte and increases the lev- el of calcium concentration in astrocyte,thus enhancing the positive feedback effect of astrocyte on neuron.In this work,we presented a neuron-astrocyte coupled model consisting of ions concentration dynamics.Our model valida- ted experimental recordings that Ca²⁺ influx through VGCCs is a major factor in the increase of Ca ²⁺ concentration in astrocyte and revealed the internal mechanism that enhanced VGCCs current could induce spontaneous epilep- tic discharges in the absence of external stimulus input.The results in this work will provide an explanation for Ca ²⁺ metabolism disorders of astrocytes can induce spontaneous epilepsy discharges.

关键词

星形胶质细胞； VGCCs ；钙离子；癫痫

Keywords

astrocyte ； VGCCs ； calcium ； seizures

0 引言
神经元产生动作电位时会导致细胞外大量的钾离子(K ⁺)和谷氨酸(Glus)积累.星形胶质细胞主要通过缓冲细胞外空间中K ⁺和Glus来调控神经元放电^[1-5].一方面,星形胶质细胞通过Kir4.1 通道摄取胞外K +的同时使细胞膜去极化,然后,去极化的星形胶质细胞刺激VGCCs打开引起钙离子(Ca ²⁺) 流入星形胶质细胞,增加了星形胶质细胞中Ca ²⁺浓度([Ca ²⁺ ] _A)水平,从而增强了星形胶质细胞对神经元的正反馈电流^[1-4].另一方面,细胞外空间“多余的”Glus与星形胶质细胞膜受体相结合,促进星形胶质细胞内IP₃浓度升高,胞内IP₃浓度升高会刺激钙库(内质网) 释放Ca ²⁺,从而提升星形胶质细胞中Ca ²⁺浓度([Ca ²⁺] A)水平,增强了对神经元的正反馈电流^[5].
星形胶质细胞静息膜电位主要依赖于K ⁺平衡电位^[6,7].星形胶质细胞Kir4.1 通道关闭或总的Kir4.1 通道打开数目减小都会使得膜电位去极化减弱(静息膜电位(E_m)) ^[8,9],Ca ²⁺内流的驱动力随之减弱,从而抑制通过VGCCs的Ca ²⁺内流^[10-12].由于通过VGCCs的Ca ²⁺内流是影响胶质细胞内Ca²⁺ 浓度的主要因素^[13],因此,星形胶质细胞VGCCs蛋白表达增强会增加胞内Ca²⁺浓度水平^{[10,11,13,23]}.实验发现,VGCCs电流增强不仅会增加星形胶质细胞内Ca²⁺浓度([Ca ²⁺ ]o),而且增加的Ca²⁺浓度瞬态幅值与星形胶质细胞膜去极化成正比^[14].另外,实验还发现,星形胶质细胞VGCCs蛋白过表达与神经元癫痫放电活动密切相关^[10,15].
由Kir4.1 通道K ⁺内流引起的星形胶质细胞膜去极化问题已有大量实验和模型进行了研究^[1,16-18].2009 年以来,陈尚宾等人给出了星形胶质细胞VGCCs电流动力学模型,数值模拟了通过VGCCs的Ca ²⁺内流是星形胶质细胞中Ca ²⁺水平增强的主要来源,但只是单独研究星形胶质细胞,且设定星形胶质细胞膜电位为一个固定参数^[24,25].另外,也有部分学者关注于Glus刺激星形胶质细胞钙库(内质网)释放Ca ²⁺而引起的胞内Ca ²⁺浓度增强调控神经元放电活动的研究^[19-22].目前,Kir4.1 通道引起的星形胶质细胞膜去极化问题､星形胶质细胞膜去极化引起VGCCs的Ca ²⁺ 内流问题､以及Glus刺激星形胶质细胞钙库释放Ca ²⁺引起的胞内Ca ²⁺浓度增强问题都是独立研究的.实际上,这三个问题是一个相互依赖的过程.
本文构建了一种考虑VGCCs钙离子电流的神经元-星形胶质细胞耦合模型,模型刻画了细胞内外钾离子,钙离子,以及钠离子代谢与星形胶质细胞膜去极化机制.首先,我们给出了VGCCs电流和星形胶质细胞内钙离子浓度与胞外钾离子和钙离子浓度之间的依赖关系，其次,我们的模拟结果验证了增强VGCCs电导会诱发神经元自发性癫痫放电活动的实验现象.
1 数学模型
神经元采用H-H模型动力学方程^[18,26,27] :

\begin{matrix} C \frac{d V_{N}}{d t} = g_{N a} m^{3} h (V_{N} - V_{N a}) - g_{K} n^{4} (V_{N} - V_{K}) - \\ g_{N a L} (V_{N} - V_{N a}) - g_{K L} (V_{N} - V_{K}) - g_{C l} (V_{N} - V_{C l}) - I_{A s t} \end{matrix}

(1)

其中,C是神经元膜电容.g_Na,g_K,gCa,g_NaL,以及g_KL 为电导值.I_Ast为星形胶质细胞的反馈电流.V_Na ､V_K 以及V_Cl为Na ⁺,K ⁺以及Cl ^-反转电位.n,m和h为门变量参数,表达式如下

\frac{d q}{d t} = φ [α_{q} (V_{N}) (1 - q) - β_{q} (V_{N}) q], q = m, n, h

(2)

$\begin{matrix} α_{m} = 0.1 (V_{N} + 30) / [1 - e x p (- 0.1 (V_{N} + 30))] \\ β_{m} = 4 e x p [- (V_{N} + 55) / 18] \\ α_{n} = 0.01 (V_{N} + 34) / [1 - e x p (- 0.1 (V_{N} + 34))] \\ β_{n} = 0.125 e x p (- (V_{N} + 44) / 80) \\ α_{h} = 0.07 e x p (- (V_{N} + 44) / 20) \\ β_{h} = 1 / [1 + e x p (- 0.1 (V_{N} + 14))] \end{matrix}$
Na⁺,K ⁺和Cl _-反转电位具体表达式为

V_{j} = 26.64 l n (\frac{[j]_{N i}}{[j]_{o}}), j = K^{+}, {N a}^{+}, {C l}^{-}

(3)

[j] _Ni和[ j]_o 表示神经元内外离子浓度(K ⁺,Na ⁺ 和Cl ^-).
1.1 钾离子平衡方程
胞外K ⁺浓度([K + ]o)的改变依赖于跨神经元膜的K ⁺ 流,K⁺ 空间扩散^[26,28],神经元与星形胶质细胞膜上的Na⁺/K ⁺-ATPase泵, 星形胶质细胞Kir4.1 通道^[18,27].通过细胞膜的电流会引起细胞内外离子浓度的变化.穿过膜的电流I等于每单位时间的离子流.因此,神经元､星形胶质细胞以及细胞外空间的K ⁺浓度动力学方程如下:

\frac{d {[K^{+}]}_{o}}{d t} = J_{I K} - 2 J_{pump, N} - 2 J_{pump, A} + J_{Kir} - J_{d i f f}

(4)

\frac{d {[K^{+}]}_{A}}{d t} = (- J_{kir} + 2 I_{pumpA}) v_{rate}

(5)

\frac{d {[K^{+}]}_{N}}{d t} = (- J_{K} + 2 J_{p u m p, N}) v_{rate}

(6)

类似于K ⁺ 浓度动力学行为, 胞外Na ⁺ 浓度([Na ⁺ ]o)的变化依赖于跨神经元膜Na ⁺流,神经元与星形胶质细胞Na ⁺/K ⁺-ATPase泵^{[17,18,26,27]}.神经元､星形胶质细胞和细胞外空间Na ⁺浓度动力学方程如下:

\frac{d {[{N a}^{+}]}_{o}}{d t} = J_{N a, N} + 3 J_{p u m p, N} + 3 J_{p u m p, A} +

(7)

J_{N a L, N} + 3 J_{N a L, A} \frac{d {[{N a}^{+}]}_{A}}{d t} = (- 3 J_{pump, A} - J_{N a L, A}) v_{r r a t e}

(8)

\frac{d [N a]_{N}}{d t} = (- J_{N a, N} - 3 J_{punmp, N} - J_{N a L, N}) v_{rate}

(9)

方程(4-9)中J_pump_,_N､J_diff和J_pump_,_A具体表达式为

\begin{matrix} J_{p u n p, N} = ρ (\frac{1}{1.0 + e x p (25.0 - {[{N a}^{+}]}_{N}) / 3.0}) \times \\ (\frac{1}{1 + e x p (8 - {[K^{+}]}_{0})}) \\ J_{d i f} = ε ({[K^{+}]}_{o} - k_{bath}) \\ J_{pump, A i} = (\frac{1}{3}) ρ (\frac{1}{1.0 + e x p (25.0 - {[{N a}^{+}]}_{A}) / 3.0}) \times \\ (\frac{1}{1 + e x p (8 - {[K^{+}]}_{0})}) \end{matrix}

(10)

其中, ρ 为Na ⁺/K ⁺-ATPase泵强度, [ Na⁺ ] _N 和 [Na ⁺ ] _A分别表示神经元和星形胶质细胞内Na ⁺浓度.ε 为K ⁺ 空间扩散系数,K_bath神经元所处电解液中得K ⁺浓度.
1.2 钙离子平衡方程
基于经典的星形胶质细胞内Ca ²⁺ 浓度([Ca ²⁺ ] A)动力学模型^{[19,21,22,29]},考虑星形胶质细胞膜去极化激活的VGCCs电流和流出星形胶质细胞的Ca ²⁺漏流.本文构建了新的[Ca ²⁺ ] A动力学方程:

\begin{matrix} \frac{d {[{C a}^{2 +}]}_{Λ}}{d t} = c_{1} v_{1} p_{\infty}^{3} n_{\infty}^{3} q^{3} ({[{C a}^{2 +}]}_{E R} - {[{C a}^{2 +}]}_{A}) + \\ c_{1} v_{2} ({[{C a}^{2 +}]}_{E R} - {[{C a}^{2 +}]}_{A}) - \\ \frac{v_{3} {[{C a}^{2 +}]}^{2}}{{[{C a}^{2 +}]}^{2} + k_{3}^{2}} + J_{V C C C s} - J_{V C C G, L} \\ \frac{d q}{d t} = α_{q} (1 - q) + β_{q} q \end{matrix}

(11)

其中,J_VGCCs与J_VGCCs_,_L分别为通过VGCCs的Ca²⁺ 流和VGCCs漏流.[Ca ²⁺ ] _ER表示星形胶质细胞内质网Ca ²⁺平衡浓度,p_∞,n_∞,α_q 以及 β_q表达式如下:

\begin{matrix} p_{\infty} = \frac{{[{I P}_{3}]}_{Λ}}{{[{I P}_{3}]}_{Λ} + d_{1}}, n_{\infty} = \frac{{[{C a}^{2 +}]}_{A}}{[{C a}^{2 +}] + d_{5}} \\ α_{q} = a_{2} d_{2} \frac{{[{I P}_{3}]}_{Λ} + d_{1}}{{[{I P}_{3}]}_{Λ} + d_{3}}, β_{q} = a_{2} {[{C a}^{2 +}]}_{A} \end{matrix}

(12)

其中,三磷酸肌醇IP₃浓度对神经元动作电位影响的方程为^[19] :

\begin{matrix} \frac{d [I P 3]_{Λ}}{d t} = & \frac{1}{τ_{I P 3}} ({[{I P}_{3}]}^{*} - {[{I P}_{3}]}_{Λ}) + \\ r_{I P 3} Θ (V_{N} - 50 m V) \end{matrix}

(13)

我们给出的细胞外空间Ca ²⁺浓度([Ca ²⁺ ]_o)动力学方程为:

\begin{matrix} \frac{d {[{C a}^{2 +}]}_{0}}{d t} = D_{C o o} ({[{C a}^{2 +}]}_{0} - C a_{b a h h}) + L_{e x} {[{C a}^{2 +}]}_{0} - \\ J_{v c c c} - M_{c a} ({[K^{+}]}_{0} - K o_{m a v / 2}) (C_{a_{o, p a t}} - C a o) (14) \end{matrix}

(14)

其中,D_Cao为Ca ²⁺空间扩散系数.Ca_bath为细胞外电解液中Ca²⁺浓度.L_ext为星形胶质细胞Ca ²⁺漏电导.Cao_rest为静息态时细胞外Ca ²⁺浓度.
方程(1) 中星形胶质细胞对神经元的反馈电流I_Ast表达式为^[19] :

\begin{matrix} I_{A A} = 2.11 Θ (y) l n (y) \\ y = l n ({[{C a}^{2 +}]}_{A} / n M - 196.69) \end{matrix}

(15)

1.3 VGCCs电流表达式
星形胶质细胞膜上VGCCs电流表达式为^[25] :

I_{v c c C s} = g_{v c C C s} m_{V c C C s} h_{V c C C s} (V_{A} - E_{C a})

(16)

其中,g_VGCCs为VGCCs电导,m_VGCCs和h_VGCCs为门控变量函数,具体表达式为
$\frac{d m_{v c C C s}}{d t} = (\bar{m_{v G C C s}} - m_{v G C C s}) / τ_{m}$
其中:
方程(16)中E_Ca为Ca ²⁺的能斯特电位,表达式为

E_Ca=(RT/zF)ln([Ca ²⁺ ]_o/[Ca ²⁺ ] _A)

(17)

1.4 星形胶质细胞膜电位动力学方程
本文构建了新的星形胶质细胞膜电位(VA)动力学方程:

C_{A} \frac{d V_{A}}{d t} = - I_{Kirt. 1} - I_{V C C C} - I_{C a, L} - I_{loak, K}

(18)

其中,CA为星形胶质细胞电容,Ikir4.1 为内向整流钾离子通道(Kir4.1)电流,具体表达式为^[27] :

I_{k i n A} = g_{k i \sqrt{l}} \sqrt{{[K^{+}]}_{0}} (V_{A} - E_{k i r} l o g ({[K^{+}]}_{0} / {[K^{+}]}_{A}))

(19)

其中g_kir和E_kir分别为Kir4.1 通道电导和能斯特常数.
2 数值结果
2.1 不同胞外K
⁺浓度时VGCCs电导影响星形胶质细胞Ca ²⁺浓度
实验发现,细胞外“高” K ⁺ 引起的星形胶质细胞膜去极化会刺激通过VGCCs的Ca ²⁺ 内流,增加星形胶质细胞内Ca ²⁺ 浓度水平^[10-13].为了验证VGCCs电流对星形胶质细胞Ca ²⁺ 浓度的重要性, 我们给出了神经元与星形胶质细胞所处电解液中K ⁺浓度(K_bath)等于5.0mM和8.0mM时,细胞外低Ca ²⁺(0.0001mM)且VGCCs阻塞(gVGCCs=0.0001pS) 时，细胞外低Ca ²⁺(0.0001mM)且VGCCs电导正常(gVGCCs=4.0pS) 时，细胞外Ca ²⁺ 浓度( 0.5mM) 和VGCCs电导(gVGCCs=4.0 pS)都正常时，以及细胞外Ca ²⁺浓度正常(0.5mM)且VGCCs电导增强( gVGCCs=74.4pS)时星形胶质细胞内Ca ²⁺浓度([Ca ²⁺ ] A) 振荡时间历程图,如图1 所示.从图1(A) 可以看出,当胞外低Ca ²⁺ 环境且VGCCs阻塞时,胞外K ⁺ 浓度升高只会使得星形胶质细胞内Ca ²⁺浓度产生非常小的微幅变化，而VGCCs正常态与阻塞态相比,VGCCs正常时的Ca ²⁺ 内流会使星形胶质细胞内Ca ²⁺浓度([Ca ²⁺ ] _A)较VGCCs阻塞时有较小的峰值增加,且星形胶质细胞内Ca²⁺浓度([Ca ²⁺] _A) 更缓慢的上升至最大峰值,如图1(A和B) 所示, 这是由于VGCCs正常时胞外“高” K ⁺ 引起星形胶质细胞膜去极化而激发VGCCs的Ca ²⁺内流需要一个时间过程.另外,VGCCs正常时,星形胶质细胞内Ca ²⁺浓度([Ca ²⁺ ] _A)在胞外Ca ²⁺浓度正常与胞外低Ca ²⁺环境相比具有一定上升幅度,如图1(B和C) 所示,这说明胞外Ca ²⁺环境也是影响星形胶质细胞内Ca ²⁺浓度([Ca ²⁺ ] _A)的一个因素.另外,我们发现胞外Ca ²⁺正常环境下,VGCCs电流增强与VGCCs电流正常时相比星形胶质细胞内Ca 2+ 浓度([Ca 2+ ] A)显著升高,如图1(C和D)所示.综上,我们得出结论,VGCCs电流是影响星形胶质细胞质中Ca²⁺浓度水平的一个主要因素.这一模拟结果与实验观察结果相一致^[10,11,13].最后,从图1 中四种条件下星形胶质细胞内Ca ²⁺ 浓度([Ca ²⁺ ] _A) 时间历程图还可以看出,每种条件下,星形胶质细胞内Ca ²⁺浓度([ Ca ²⁺ ] _A) 幅值在细胞外环境K ⁺ 浓度(K_bath)等于8mM时都比5mM时显著升高.
图1 不同细胞外K⁺ 浓度(K_bath) 时,星形胶质细胞内Ca²⁺ 浓度([Ca²⁺ ] _A)依赖于VGCCs电导(gVGCCs)和细胞外Ca ²⁺浓度(Cabath).
Fig.1 Astrocyte Ca ²⁺ concentration([ Ca ²⁺ ] A) depends on the con-ductance of VGCCs( gVGCCs) and extracellular calcium concentration(C_abath)with different extracellular potassium concentration(K_bath).
另外,对应图1 中四种情况,我们给出了胞外K ⁺浓度K_bath 从5.0mM升高至8.0mM,细胞外低Ca ²⁺( 0.0001mM) 且VGCCs阻塞( gVGCCs=0.0001 pS)时(图2(A))，细胞外低Ca ²⁺( 0.0001mM) 且VGCCs电导正常(gVGCCs=4.0 pS)时(图2(B))，细胞外Ca ²⁺浓度(0.5mM)和VGCCs电导(gVGCCs=4.0 pS)都正常时(图2(C))，以及细胞外Ca ²⁺浓度正常(0.5mM) 且VGCCs电导增强( gVGCCs=74.4 pS图2(D)) 时星形胶质细胞膜去极化动作电位(VA)与胞内Ca ²⁺浓度瞬态幅值的相关曲线,如图2 所示.从图2 中我们发现,不论细胞外低Ca ²⁺环境还是Ca ²⁺浓度正常,细胞外环境K ⁺ 浓度(K_bath) 升高会使得星形胶质细胞膜去极化程度与胞内Ca ²⁺ 浓度幅值增加,且星形胶质细胞内Ca ²⁺浓度的瞬态幅值与星形胶质细胞膜去极化幅值成正比.这说明细胞外K ⁺浓度升高是诱发星形胶质细胞膜去极化的主要因素.而且,从图2(A和B)与图2(C和D) 中可以发现,相同细胞外K ⁺环境时,不论细胞外低Ca ²⁺环境还是Ca ²⁺ 浓度正常,VGCCs电导( gVGCCs) 增强都会使星形胶质细胞膜去极化增强且胞内Ca ²⁺浓度瞬态幅值增加.特别地,胞外环境中Ca ²⁺浓度正常时,VGCCs电导增强会使星形胶质细胞膜产生非常剧烈的去极化现象,如图2(C和D)所示.这说明细胞星形胶质细胞膜去极化还依赖于细胞外环境中Ca ²⁺浓度和VGCCs电导的强度.
2.2 VGCCs
电流增强诱导癫痫放电
实验发现,VGCCs电流增强与神经系统癫痫放电密切相关^[10].本节给出了没有外界刺激输入时
图2 随着细胞外K⁺浓度升高,星形胶质细胞膜电压(VA)与胞内Ca ²⁺浓度([Ca ²⁺ ] A)瞬态幅值与成正比,且依赖于细胞外Ca ²⁺浓度和VGCCs电流.
Fig.2 As extracellular K ⁺ concentration increasing,astrocyte membrane potential(VA) is proportional to the transients amplitude of astrocyte Ca ²⁺ concentration([ Ca ²⁺ ] A) and dependent on extracellular Ca ²⁺ concentration and VGCCs currents.
VGCCs电导( g_{VGCC s}) 增强诱发神经元癫痫放电的临界阈值.模拟结果表明,没有外部刺激输入时,当gVGCC>4.6pS时会诱发神经元产生自发性类癫痫活动(图3 红色线条).这种癫痫放电活动是以2-15s的“Depolarization block” 为特征,与Bikson等人在大鼠海马切片电生理实验中观察的结果相一致(图1(D),^[30]).图3 给出了g_VGCCs=4 pS(图3,黑色线条)和74.4 pS(图3,红色线条)时神经元与星形胶质细胞膜电位､细胞外K ⁺浓度､星形胶质细胞内K ⁺浓度､Ca ²⁺浓度､以及IP₃浓度的时间序列.我们发现,gVGCCs过大(gVGCCs=74.4 pS)时神经元处于自发性癫痫放电(图3(A)),对应的细胞外K ⁺ 浓度 [K ⁺ ]_o会产生更高的振荡幅值(接近40mM图3(C)),同时,星形胶质细胞膜产生强的去极化膜电位(图3(B)),而且,星形胶质细胞内K ⁺浓度(图3(D))､Ca ²⁺ 浓度(图3( E))､以及IP³ 浓度( 图3(F))都有非常大的振荡幅值.另外,从图3(C和D)中还可以看出,自发性癫痫放电对应的胞外K ⁺
图3 没有外界刺激输入时,VGCCs电导gVGCCs增大会诱发神经元产生自发癫痫放电.当gVGCCs等于74.4pS(红色线条)和4pS(黑色线条)时,神经元膜电位(V_N),星形胶质细胞膜电位( V_A)､细胞外空间K ⁺浓度([K ⁺ ] _o)､星形胶质细胞内K ⁺浓度([K ⁺ ] _A)､星形胶质细胞内Ca ²⁺ 浓度([ Ca ²⁺ ] _A)､以及星形胶质细胞内IP₃ 浓度([IP₃ ] _A 的时间序列.
Fig.3 Increased astrocytic VGCCs conductance gVGCCs induces sponta-neous epileptic seizures in the absence of external stimuli.Time trains of the neural(V_N) and astrocytic membrane potential( V_A),extracellular K ⁺ concentration([K ⁺ ] _o),K + concentration([K ⁺ ] _A) and Ca ²⁺ con-centration([Ca ²⁺ ] _A) and IP₃([IP₃ ] _A) in astrocyte when gVGCCs is 4.0pS((black lines) and 74.4pS(red lines).
浓度不仅需要更长的时间回到基线,且星形胶质细胞内K ⁺ 浓度缓慢上升到较低的K ⁺ 浓度峰值(与gVGCCs=4.0pS时相比).
3 结论
考虑星形胶质细胞膜去极化激活的VGCCs钙离子电流,本文构建了一种神经元-星形胶质细胞耦合模型,模型详细刻画了细胞内外钾离子,钙离子,以及钠离子代谢与星形胶质细胞膜去极化机制.数值模拟结果论证了VGCCs电流是影响星形胶质细胞中钙离子浓度水平的一个主要因素^[11,13]，发现随着细胞外环境中钾离子浓度的升高,星形胶质细胞内钙离子瞬态幅值与胶质细胞膜去极化成正比，并且星形胶质细胞膜去极化与胞内钙离子浓度的升高还依赖于细胞外空间钙离子浓度与VGCCs电导的增强.另外,数值模拟结果还验证了VGCCs电导增加会诱发神经元产生自发性癫痫放电的实验结果^[10].给出了VGCCs电流增强诱发癫痫的机制:VGCCs电导增加会使得星形胶质细胞内钙离子浓度振荡幅值增加,导致星形胶质细胞对神经元的正反馈作用增强,从而提高神经元的兴奋性,最终导致胞外钾离子“过量”诱发癫痫.
本文旨在建立考虑钠离子和钾离子代谢的神经元-星形胶质细胞耦合模型,研究星形胶质细胞电压门控钙离子通道电流增强改变星形胶质细胞胞内钙离子浓度诱发神经系统癫痫放电的内在机制.为替代药物作用在神经元上对人体的负面影响^[31],从调控星形胶质细胞电压门控钙离子通道改变星形胶质细胞钙离子水平作为治疗癫痫疾病的新靶点提供理论指导.
参考文献
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基本信息

DOI: 10.6052/1672-6553-2020-012
文章编号: 1672-6553/2020/18⑴/049-07

基金信息

国家自然科学基金资助项目(11772242)；

引用信息

稿件历史

收稿日期: 2019-08-30

参考文献

[1] Ohno Y,Tokudome K,Kunisawa N,et al.Role of astro-glial Kir4.1 channels in the pathogenesis and treatment of epilepsy.Therapeutic Targets for Neurological Diseases,2015,2:1~ 10
[2] Kucheryavykh Y V,Kucheryavykh L Y,Nichols C G,et al.Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes.Glia,2007,55(3):274~ 281
[3] Seifert G,Steinhäuser C.Neuron-astrocyte signaling and epilepsy.Experimental Neurology,2013,244(6):4~ 10
[4] Butt A M,Kalsi A.Inwardly rectifying potassium channels(Kir)in central nervous system glia:a special role for Kir4.1 in glial functions.Journal of cellular and molecular medicine,2006,10(1):33~ 44
[5] Volman V,Bazhenov M,Sejnowski T J.Computational models of neuron-astrocyte interaction in epilepsy.Fron-tiers in Computational Neuroscience,2012,6:58
[6] Walz W,Hertz L.Intracellular ion changes of astrocytes in response to extracellular potassium.Journal of Neuro-science Research,1983,10(4):411~ 423
[7] Walz W,Hertz L.Intense furosemide-sensitive potassium accumulation in astrocytes in the presence of pathological-ly high extracellular potassium levels.Journal of Cereb Blood Flow Metab,1984,4(2):301~ 304
[8] Fleischmann B K,Washabau R J,Kotlikoff M I.Control of resting membrane potential by delayed rectifier potassi-um currents in ferret airway smooth muscle cells.The Journal of Physiology,1993,469(1):625~ 638
[9] Isom L.Auxiliary subunits of voltage-gated ion channels.Neuron,1994,12(6):1183~ 1194
[10] Westenbroek R.Upregulation of L-type Ca 2+ channels in reactive astrocytes after brain injury,hypomyelination,and ischemia.The Journal of Neuroscience,1998,18(7):2321ports,2016,6:30914-34
[11] MacVicar B.Voltage-dependent calcium channels in glial cells.Science,1984,226(4680):1345~ 1347
[12] Duffy S,Macvicar B A.In vitro ischemia promotes calci-um influx and intracellular calcium release in hippocampal astrocytes.The Journal of Neuroscience,1996,16(1):71 ~ 81
[13] Duffy S,MacVicar B A.Potassium-dependent calcium in-flux in acutely isolated hippocampal astrocytes.Neuro-science,1994,61(1):51~ 61
[14] Bezzi P,Carmignoto G,Pasti L,et al.Prostaglandins stimulate calcium-dependent glutamate release in astro-cytes.Nature,1998,391(6664):281~ 285
[15] Gómez-Gonzalo,Marta,Losi G,et al.An excitatory loop with astrocytes contributes to drive neurons to seizure Threshold.Plos Biology,2010,8(4):e1000352
[16] Heuser K,Eid T,Lauritzen F,et al.Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy.Journal of Neuropathology & Experimental Neurology,2012,71(9):814~ 825
[17] Sibille,Jérémie,Dao Duc K,et al.The neuroglial potas-sium cycle during neurotransmission:role of Kir4.1 chan-nels.Plos Computational Biology,2015,11(3):e1004137
[18] Mengmeng D,Jiajia L,Liang C,et al.Astrocytic Kir4.1 channels and gap junctions account for spontaneous epi-leptic seizure.Plos Computational Biology,2018,14(3):e1005877
[19] Nadkarni S,Jung P.Spontaneous oscillations of dressed neurons:a new mechanism for epilepsy?Physical Review Letters,2003,91(26 Pt 1):268101
[20] 刘建,杨利建,刘望恒,等.星形胶质细胞引起神经元超激发的作用机制分析.生物物理学报,2011,27(1):57~ 65(Liu J,Yang J L,Liu W H,et al.An analysis on the mechanism of astrocytes cause neuronal hyper-excitability.Acta Biophysica Sinica,2011,27(1):57 ~ 65(in Chi-nese))
[21] Li J,Wang R,Du M,et al.Dynamic transition on the seizure-like neuronal activity by astrocytic calcium channel block.Chao,Solitons & Fractals,2016,91:702~ 708
[22] Li J,Tang J,Ma J,et al.Dynamic transition of neuronal firing induced by abnormal astrocytic glutamate oscillation.Scientific Reports,2016,6(1):32343
[23] 王磊,蔡景霞.星形胶质细胞存在L型钙通道的新证据.动物学研究,2007,28(5):38(Wang L,Cai J X.New proof for astrocytes having L-type calcium channels.Zoo-logical Research,2007,28(5):38(in Chinese))
[24] Zeng S,Li B,Zeng S,et al.Simulation of spontaneous Ca 2+ oscillations in astrocytes mediated by voltage-gated calcium channels.Biophysical Journal,2009,97(9):2429~ 2437
[25] Li B,Chen S,Zeng S,et al.Modeling the contributions of Ca 2+ flows to spontaneous Ca 2+ oscillations and corticalspreading depression-triggered Ca 2+ waves in astrocyte net-works.Plos One,2012,7(10):e48534
[26] Jr J R C,Ullah G,Ziburkus J,et al.The influence of so-dium and potassium dynamics on excitability,seizures,and the stability of persistent states:I.Single neuron dynamics.Journal of Computational Neuroscience,2009,26(2):159 ~ 70
[27] Du M,Li J,Wang R,et al.The influence of potassium concentration on epileptic seizures in a coupled neuronal model in the hippocampus.Cognitive Neurodynamics,2016,10(5):405~ 414
[28] Ullah G,Cressman J R,Barreto E,et al.The influence of sodium and potassium dynamics on excitability,seizures,and the stability of persistent states:II.Network and glial dynamics.Journal of Computational Neuroscience,2009,26(2):171~ 183
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星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电∗

VOlTAGE-GATED CALCIUM CHANNELS IN ASTRCOCYTES REGULATING EPILEPTIC SEIZURES ∗

摘要

Abstract

关键词

Keywords

0 引言

1 数学模型

(1)

(2)

(3)

1.1 钾离子平衡方程

(4)

(5)

(6)

(7)

(8)

(9)

(10)

1.2 钙离子平衡方程

(11)

(12)

(13)

(14)

(15)

1.3 VGCCs电流表达式

(16)

(17)

1.4 星形胶质细胞膜电位动力学方程

(18)

(19)

2 数值结果

2.1 不同胞外K

2.2 VGCCs

3 结论

参考文献

基本信息

基金信息

引用信息

稿件历史

参考文献

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星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电^∗

VOlTAGE-GATED CALCIUM CHANNELS IN ASTRCOCYTES REGULATING EPILEPTIC SEIZURES ^∗