Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA-dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression.
Chronic stress is a precipitating factor for disorders including depression. The basolateral amygdala (BLA) is a critical substrate that interconnects with stress-modulated neural networks to generate emotion- and mood-related behaviors. The current study shows that 3 h per day of restraint stress for 14 days caused mice to exhibit long-term depressive behaviors, manifested by disrupted sociality and despair levels, which were rescued by fluoxetine. These behavioral changes corresponded with morphological and molecular changes in BLA neurons, including chronic stress-elicited increases in arborization, dendritic length, and spine density of BLA principal neurons. At the molecular level, calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) within the synaptosome exhibited an increased GluR1:GluR2 subunit ratio. We also observed increased GluR1 phosphorylation at Ser 845 and enhanced cyclic AMP-dependent protein kinase (PKA) activity in the BLA. These molecular changes reverted to the basal state post-treatment with fluoxetine. The expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95) at BLA neuronal synapses was also enhanced by chronic stress, which was reversed post-treatment. Finally, chronic stress-provoked depressive behavior was overcome by local blockage of CP-AMPARs in the BLA via stereotaxic injection (IEM-1460). Chronic stress-elicited depressive behavior may be due to hypertrophy of BLA neuronal dendrites and increased of PKA-dependent CP-AMPAR levels in BLA neurons. Furthermore, fluoxetine can reverse chronic stress-triggered cytoarchitectural and functional changes of BLA neurons. These findings provide insights into depression-linked structural and functional changes in BLA neurons.
Department of Exercise Rehabilitation & Welfare, Gachon University, Incheon, Republic of Korea.
Eun-Surk
ES
Yi
Department of Molecular Medicine and TIDRC, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Seikwan
S
Oh
Department of Physical Education, Dankook University, Cheonan-si, Chungnam-do 330-951, Republic of Korea.
Jang-Kyu
JK
Lee
Department of Molecular Medicine and TIDRC, School of Medicine, Ewha Womans University, Seoul, Republic of Korea. Electronic address: leemyy@empas.com.
Yea-Hyun
YH
Leem
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D003863:Depression / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000218:Adamantane; D000928:Antidepressive Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D000076122:Disks Large Homolog 4 Protein; D005473:Fluoxetine; D051528:Guanylate Kinases; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016708:Synaptophysin; C501447:Dlg4 protein, mouse; C110702:IEM 1460; C569015:Syp protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2
BLA; CP-AMPAR; Chronic restraint stress; Dendritic remodeling; Depression; PKA