McCarthy Michelle M, Brown Emery N, Kopell Nancy
Department of Mathematics and Statistics, Boston University, Boston, Massachusetts 02215, USA.
J Neurosci. 2008 Dec 10;28(50):13488-504. doi: 10.1523/JNEUROSCI.3536-08.2008.
Propofol, like most general anesthetic drugs, can induce both behavioral and electroencephalographic (EEG) manifestations of excitation, rather than sedation, at low doses. Neuronal excitation is unexpected in the presence of this GABA(A)-potentiating drug. We construct a series of network models to understand this paradox. Individual neurons have ion channel conductances with Hodgkin-Huxley-type formulations. Propofol increases the maximal conductance and time constant of decay of the synaptic GABA(A) current. Networks range in size from 2 to 230 neurons. Population output is measured as a function of pyramidal cell activity, with the electroencephalogram approximated by the sum of population AMPA activity between pyramidal cells. These model networks suggest propofol-induced paradoxical excitation may result from a membrane level interaction between the GABA(A) current and an intrinsic membrane slow potassium current (M-current). This membrane level interaction has consequences at the level of multicellular networks enabling a switch from baseline interneuron synchrony to propofol-induced interneuron antisynchrony. Large network models reproduce the clinical EEG changes characteristic of propofol-induced paradoxical excitation. The EEG changes coincide with the emergence of antisynchronous interneuron clusters in the model networks. Our findings suggest interneuron antisynchrony as a potential network mechanism underlying the generation of propofol-induced paradoxical excitation. As correlates of behavioral phenomenology, these networks may refine our understanding of the specific behavioral states associated with general anesthesia.
与大多数全身麻醉药物一样，丙泊酚在低剂量时会引发行为和脑电图（EEG）的兴奋表现，而非镇静作用。在这种增强GABA(A)作用的药物存在的情况下，神经元兴奋是出乎意料的。我们构建了一系列网络模型来理解这一矛盾现象。单个神经元具有用霍奇金-赫胥黎型公式表示的离子通道电导。丙泊酚增加了突触GABA(A)电流的最大电导和衰减时间常数。网络规模从2个神经元到230个神经元不等。群体输出作为锥体细胞活动的函数进行测量，脑电图由锥体细胞之间群体AMPA活动的总和近似表示。这些模型网络表明，丙泊酚诱导的矛盾性兴奋可能源于GABA(A)电流与内在膜慢钾电流（M电流）之间的膜水平相互作用。这种膜水平相互作用在多细胞网络水平上产生影响，使得从基线中间神经元同步转变为丙泊酚诱导的中间神经元反同步。大型网络模型再现了丙泊酚诱导的矛盾性兴奋所特有的临床脑电图变化。脑电图变化与模型网络中反同步中间神经元簇的出现相一致。我们的研究结果表明，中间神经元反同步是丙泊酚诱导的矛盾性兴奋产生的潜在网络机制。作为行为现象学的相关因素，这些网络可能会完善我们对与全身麻醉相关的特定行为状态的理解。
