Montalbano Alberto, Waider Jonas, Barbieri Mario, Baytas Ozan, Lesch Klaus-Peter, Corradetti Renato, Mlinar Boris
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
Eur Neuropsychopharmacol. 2015 Nov;25(11):2022-35. doi: 10.1016/j.euroneuro.2015.08.021. Epub 2015 Sep 11.
Considerable evidence links dysfunction of serotonin (5-hydroxytryptamine, 5-HT) transmission to neurodevelopmental and psychiatric disorders characterized by compromised "social" cognition and emotion regulation. It is well established that the brain 5-HT system is under autoregulatory control by its principal transmitter 5-HT via its effects on activity and expression of 5-HT system-related proteins. To examine whether 5-HT itself also has a crucial role in the acquisition and maintenance of characteristic rhythmic firing of 5-HT neurons, we compared their intrinsic electrophysiological properties in mice lacking brain 5-HT, i.e. tryptophan hydroxylase-2 null mice (Tph2(-/-)) and their littermates, Tph2(+/-) and Tph2(+/+), by using whole-cell patch-clamp recordings in a brainstem slice preparation and single unit recording in anesthetized animals. We report that the active properties of dorsal raphe nucleus (DRN) 5-HT neurons in vivo (firing rate magnitude and variability; the presence of spike doublets) and in vitro (firing in response to depolarizing current pulses; action potential shape) as well as the resting membrane potential remained essentially unchanged across Tph2 genotypes. However, there were subtle differences in subthreshold properties, most notably, an approximately 25% higher input conductance in Tph2(-/-) mice compared with Tph2(+/-) and Tph2(+/+) littermates (p<0.0001). This difference may at least in part be a consequence of slightly bigger size of the DRN 5-HT neurons in Tph2(-/-) mice (approximately 10%, p<0.0001). Taken together, these findings show that 5-HT neurons acquire and maintain their signature firing properties independently of the presence of their principal neurotransmitter 5-HT, displaying an unexpected functional resilience to complete brain 5-HT deficiency.
大量证据表明，血清素（5-羟色胺，5-HT）传递功能障碍与以“社交”认知和情绪调节受损为特征的神经发育和精神疾病有关。众所周知，大脑5-HT系统受其主要递质5-HT的自身调节控制，5-HT通过影响与5-HT系统相关蛋白的活性和表达来实现这一控制。为了研究5-HT自身在5-HT神经元特征性节律性放电的获得和维持中是否也起关键作用，我们通过在脑干切片标本中使用全细胞膜片钳记录以及在麻醉动物中进行单单位记录，比较了缺乏大脑5-HT的小鼠（即色氨酸羟化酶-2基因敲除小鼠，Tph2(-/-)）及其同窝小鼠（Tph2(+/-)和Tph2(+/+)）中5-HT神经元的内在电生理特性。我们报告称，在体内（放电频率大小和变异性；尖峰双峰的存在）和体外（对去极化电流脉冲的放电；动作电位形状），背侧中缝核（DRN）5-HT神经元的活性特性以及静息膜电位在不同Tph2基因型之间基本保持不变。然而，阈下特性存在细微差异，最显著的是，与Tph2(+/-)和Tph2(+/+)同窝小鼠相比，Tph2(-/-)小鼠的输入电导大约高25%（p<0.0001）。这种差异可能至少部分是由于Tph2(-/-)小鼠中DRN 5-HT神经元的尺寸略大（约10%，p<0.0001）。综上所述，这些发现表明，5-HT神经元获得并维持其特征性放电特性独立于其主要神经递质5-HT的存在，显示出对完全性大脑5-HT缺乏具有意想不到的功能弹性。
