title: Downregulation of neuregulin 1-ErbB4 signaling in parvalbumin interneurons in the rat brain may contribute to the antidepressant properties of ketamine.
abstract: Increasing evidence underscores the strong, rapid, and sustained antidepressant properties of ketamine with a good tolerability profile in patients with depression; however, the underlying mechanisms are not fully elucidated. Neuregulin 1 (NRG1) is a bipolar disorder susceptibility gene and a biomarker of major depressive disorder, which regulates pyramidal neuron activity via ErbB4 in parvalbumin interneurons. Moreover, NRG1-ErbB4 signaling is reported to play a key role in the modulation of synaptic plasticity through regulating the neurotransmission. We therefore hypothesized that hypofunction of NRG1-ErbB4 signaling in parvalbumin interneurons is involved in the process of ketamine exerting rapid antidepressant actions in rats subjected to the forced swimming test (FST). The results showed that ketamine reduced the immobility time and latency to feed of rats receiving the FST, downregulated the levels of NRG1, phosphorylated ErbB4 (p-ErbB4), parvalbumin, 67-kDA isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid (GABA), and upregulated the levels of glutamate in the rat prefrontal cortex and hippocampus. Pretreatment with NRG1 abolished both ketamine's antidepressant effects and ketamine-induced reduction in p-ErbB4, parvalbumin, GAD67, and GABA levels and increase in glutamate levels. These results suggest that the downregulation of NRG1-ErbB4 signaling in parvalbumin interneurons in the rat brain may be a mechanism underlying ketamine's antidepressant properties.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Guang-Fen
authors.initials: GF
authors.lastname: Zhang
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: He-Liang
authors.initials: HL
authors.lastname: Sun
authors.forename: Xing-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Qiu
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008124:Locomotion; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D010320:Parvalbumins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1