Modulation of Burst Firing of Neurons in Nucleus Reticularis of the Thalamus by GluN2C-Containing NMDA Receptors
Modulation of Burst Firing of Neurons in Nucleus Reticularis of the Thalamus by GluN2C-Containing NMDA Receptors
复制标题
DOI：
10.1124/mol.119.116780
复制
发表时间：
2019-08-01
影响因子：
3.6
通讯作者：
Dravid, Shashank M.
中科院分区：
文献类型：
--
作者：
Liu, Jinxu;Shelkar, Gajanan P.;Dravid, Shashank M.
NMDA受体的GluN2C亚基在丘脑网状核(NRT)的神经元中含量丰富，但其调节功能的作用尚不清楚。我们发现，GluN2C亚单位的缺失并不影响NRT神经元对去极化电流注入或超极化诱发的反弹爆发放电的反应的峰频率。D-环丝氨酸或CIQ(GluN2C/GluN2D正变构调节剂)不影响NRT神经元去极化诱发的放电频率。新近发现的一种高效、高效的GluN1/GluN2CNMDA受体共激动剂AICPNMDA酸(((R)-2-amino-3-(4(2-ethylpheny1)-1H-indole-2-carboxannido)propanoic酸)能降低野生型NRT神经元的峰频率和突触放电，但不能降低GIuN2C基因敲除的神经元的放电频率。这种作用可能是由于含有GIuN2C的受体的易化，因为AP5抑制NMDA受体并不影响NRT神经元的尖峰频率。我们评价了脑室注射AICP的效果。AICP不影响基础运动或脉冲前抑制，但促进了MK-801诱导的超运动。这一效应在野生型GIuN2C基因敲除小鼠中观察到，但在GIuN2C基因敲除小鼠中没有观察到，表明AICP在体内产生GluN2C选择性效应。利用化学遗传学方法，我们研究了NRT在这种行为效应中的作用。用Cre依赖的病毒载体和PV-Cre小鼠系选择性地在NRT神经元中表达G(Q)或G(I)偶联的DREADD。我们发现，类似于AICP效应，激活G(Q)而不是G(I)偶联的DREADD促进了MK-801诱导的多动。综上所述，这些结果确定了含有GluN2C的受体在调节NRT神经元中的独特作用，并提示AICPGIuN2C选择性体内靶向NMDA受体。
The GluN2C subunit of the NMDA receptor is enriched in the neurons in the nucleus reticularis of the thalamus (nRT), but its role in regulating their function is not well understood. We found that deletion of GluN2C subunit did not affect spike frequency in response to depolarizing current injection or hyperpolarization-induced rebound burst firing of nRT neurons. D-Cycloserine or CIQ (GluN2C/GluN2D positive allosteric modulator) did not affect the depolarization-induced spike frequency in nRT neurons. A newly identified highly potent and efficacious coagonist of GluN1/GluN2C NMDA receptors, AICP ((R)-2-amino-3-(4(2-ethylpheny1)-1H-indole-2-carboxannido)propanoic acid), was found to reduce the spike frequency and burst firing of nRT neurons in wild type but not GIuN2C knockout. This effect was potentially due to facilitation of GIuN2C-containing receptors, because inhibition of NMDA receptors by AP5 did not affect spike frequency in nRT neurons. We evaluated the effect of intracerebroventricular injection of AICP. AICP did not affect basal locomotion or prepulse inhibition but facilitated MK-801-induced hyperlocomotion. This effect was observed in wild-type but not in GIuN2C knockout mice, demonstrating that AICP produces GluN2C-selective effects in vivo. Using a chemogenetic approach, we examined the role of nRT in this behavioral effect. G(q)- or G(i)-coupled DREADDs were selectively expressed in nRT neurons using Cre-dependent viral vectors and PV-Cre mouse line. We found that similar to AICP effect, activation of G(q)- but not G(i)-coupled DREADD facilitated MK-801-induced hyperlocomotion. Together, these results identify a unique role of GluN2C-containing receptors in the regulation of nRT neurons and suggest GIuN2C-selective in vivo targeting of NMDA receptors by AICP.