Phencyclidine-induced decrease of synaptic connectivity via inhibition of BDNF secretion in cultured cortical neurons

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 23; no. 4; pp. 847 - 858
• Main Authors: Adachi, Naoki, Numakawa, Tadahiro, Kumamaru, Emi, Itami, Chiaki, Chiba, Shuichi, Iijima, Yoshimi, Richards, Misty, Katoh-Semba, Ritsuko, Kunugi, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States 01-04-2013
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Biophysics; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Calcium - metabolism; Cells, Cultured; Cerebral Cortex - cytology; Excitatory Amino Acid Antagonists - pharmacology; Gene Expression Regulation - drug effects; Nerve Tissue Proteins - metabolism; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurotransmitter Agents - metabolism; Patch-Clamp Techniques; Phencyclidine - pharmacology; Rats; Rats, Wistar; Receptor, trkB - metabolism; Receptors, Glutamate - genetics; Receptors, Glutamate - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; Synapses - drug effects; Synaptic Potentials - drug effects; Tetrazolium Salts - metabolism; Thiazoles - metabolism; Time Factors
• ISSN: 1047-3211; 1460-2199
• DOI: 10.1093/cercor/bhs074

Repeated administration of phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker, produces schizophrenia-like behaviors in humans and rodents. Although impairment of synaptic function has been implicated in the effect of PCP, the molecular mechanisms have not yet been elucidated. Considering that brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity, we examined whether exposure to PCP leads to impaired BDNF function in cultured cortical neurons. We found that PCP caused a transient increase in the level of intracellular BDNF within 3 h. Despite the increased intracellular amount of BDNF, activation of Trk receptors and downstream signaling cascades, including MAPK/ERK1/2 and PI3K/Akt pathways, were decreased. The number of synaptic sites and expression of synaptic proteins were decreased 48 h after PCP application without any impact on cell viability. Both electrophysiological and biochemical analyses revealed that PCP diminished glutamatergic neurotransmission. Furthermore, we found that the secretion of BDNF from cortical neurons was suppressed by PCP. We also confirmed that PCP-caused downregulation of Trk signalings and synaptic proteins were restored by exogenous BDNF application. It is possible that impaired secretion of BDNF and subsequent decreases in Trk signaling are responsible for the loss of synaptic connections caused by PCP.