Garcia-Garcia Alvaro L, Elizalde Natalia, Matrov Denis, Harro Jaanus, Wojcik Sonja M, Venzala Elisabet, Ramírez Maria J, Del Rio Joaquin, Tordera Rosa M
Department of Pharmacology, University of Navarra, Pamplona 31080, Spain.
Biol Psychiatry. 2009 Aug 1;66(3):275-82. doi: 10.1016/j.biopsych.2009.02.027. Epub 2009 May 1.
Many studies link depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/gamma-aminobutyric acid (GABA) cycle may account for this imbalance. Evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affect the glutamate/GABA cycle and induce helpless behavior. We studied decreased VGLUT1 as a potential factor enhancing a depressive-like phenotype in an animal model.
Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the VGLUT1+/- and wildtype. The regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle, and behavior by both genotype and chronic mild stress (CMS) were studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was studied.
VGLUT1+/- mice showed increased neuronal synthesis of glutamate; decreased cortical and hippocampal GABA, VGLUT1, and excitatory amino acid transporter 1 (EAAT1) as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, the vesicular GABA transporter (VGAT), and glutamic acid decarboxylase 65 (GAD65) in both areas and led to upregulation of EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety, and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown.
These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress.
许多研究将抑郁症与前脑兴奋性-抑制性比率的增加联系起来。谷氨酸/γ-氨基丁酸（GABA）循环共同通路中的突触前改变可能是这种失衡的原因。有证据表明，前脑小泡谷氨酸转运体1（VGLUT1）水平降低会影响谷氨酸/GABA循环并诱发无助行为。我们研究了VGLUT1降低作为动物模型中增强抑郁样表型的潜在因素。
研究了VGLUT1+/-杂合小鼠和野生型小鼠的谷氨酸和GABA合成以及氧化代谢。研究了基因型和慢性轻度应激（CMS）对神经递质水平、参与谷氨酸/GABA循环的蛋白质以及行为的调节作用。最后，研究了慢性丙咪嗪对VGLUT1调控和CMS小鼠的影响。
VGLUT1+/-小鼠的神经元谷氨酸合成增加；皮质和海马GABA、VGLUT1和兴奋性氨基酸转运体1（EAAT1）减少，同时出现无助和快感缺失。CMS导致两个区域的谷氨酸增加，GABA、小泡GABA转运体（VGAT）和谷氨酸脱羧酶65（GAD65）减少，并导致海马中EAAT1上调。此外，CMS诱发快感缺失、无助、焦虑和认知记忆受损。VGLUT1+/- CMS小鼠表现出联合表型（基因型加应激）和特定改变，如VGLUT2上调和活动亢进。此外，还显示出对慢性丙咪嗪可逆转的快感缺失和无助的易感性增加。
这些研究突出了前脑VGLUT1降低作为慢性轻度应激易感性增加的生物学介导因素的关键作用。
