Reduced serotonin impairs long-term depression in basolateral amygdala complex and causes anxiety-like behaviors in a mouse model of perimenopause

Ya Wang; Yang Liu; Jianwei Xiong; Tingting Di; Zihao Yuan; Jie Wu; Ling Chen

doi:10.1016/j.expneurol.2019.113030

Reduced serotonin impairs long-term depression in basolateral amygdala complex and causes anxiety-like behaviors in a mouse model of perimenopause

Exp Neurol. 2019 Nov:321:113030. doi: 10.1016/j.expneurol.2019.113030. Epub 2019 Aug 1.

Authors

Ya Wang¹, Yang Liu², Jianwei Xiong², Tingting Di¹, Zihao Yuan³, Jie Wu⁴, Ling Chen⁵

Affiliations

¹ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
² Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
³ Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
⁴ Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: wujiemd@126.com.
⁵ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Physiology, Nanjing Medical University, Nanjing 211166, China. Electronic address: lingchen@njmu.edu.cn.

PMID: 31377402
DOI: 10.1016/j.expneurol.2019.113030

Abstract

Perimenopause is characterized by a gradual depletion of ovarian follicles with increased vulnerability to anxiety. However, the underlying mechanisms remain poorly understood. Herein, we show that chronic exposure to 4-vinylcycloxene diepoxide (VCD) in adult female mice (VCD-mice) caused follicles depletion and decline of serum estradiol (E2) and progesterone levels. Serotonin (5-HT) synthesis in dorsal raphe nucleus (DRN) and serotonergic afferents to basolateral amygdala complex (BLA) were reduced in VCD-mice, which were recovered by the supplement E2. VCD-mice appeared anxiety-like behaviors, which was relieved by the treatment with E2 or the co-administration of 5-HT1Ar agonist 8-OH-DPAT and 5-HT2A/Cr agonist DOI. The bath-application of 8-OH-DPAT in the slices obtained from VCD-mice (VCD-slices) corrected the increase in presynaptic glutamate release at external capsule-BLA synaptic transmission. Threshold to induce NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was declined in VCD-mice with elevation of CaMKII phosphorylation, which was sensitive to 8-OH-DPAT. Notably, the bath-application of 8-OH-DPAT in VCD-slices caused a decrease in the GABAergic feedback inhibition, which was restored by adding DOI. In addition, NMDAr-independent long-term depression (LTD) could not be induced in VCD-mice, which was rescued by the co-application of 8-OH-DPAT with DOI or the GABA_A receptor agonist muscimol. Furthermore, the treatment of VCD-mice with E2 could prevent the facilitation of LTP and recover the LTD induction. Thus, the results indicate that the 5-HT deficiency in the BLA of VCD-mice causes the facilitation of LTP via enhanced glutamate release and impairs the LTD induction through diminished GABAergic inhibition, leading to anxiety-like behaviors.

Keywords: Anxiety-like behaviors; Basolateral amygdala complex; Long-term depression; Long-term potentiation; Perimenopause; Serotonin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety / physiopathology*
Basolateral Nuclear Complex / metabolism*
Basolateral Nuclear Complex / physiopathology
Disease Models, Animal
Female
Long-Term Synaptic Depression / physiology*
Mice
Mice, Inbred ICR
Perimenopause / metabolism*
Serotonin / metabolism*

Substances

Serotonin