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

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Phencyclidine (PCP), an NMDA receptor antagonist, induces schizophrenia-like behaviors.
• Synaptic function impairment is linked to PCP effects, but molecular mechanisms remain unclear.
• Brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity.

Purpose of the Study:

• To investigate if PCP exposure impairs BDNF function in cultured cortical neurons.
• To elucidate the molecular mechanisms underlying PCP's effects on synaptic function.

Main Methods:

• Primary cortical neuron cultures were treated with PCP.
• Intracellular BDNF levels, Trk receptor activation, and downstream signaling (MAPK/ERK1/2, PI3K/Akt) were assessed.
• Synaptic site number, synaptic protein expression, and glutamatergic neurotransmission were analyzed.
• BDNF secretion and effects of exogenous BDNF were evaluated.

Main Results:

• PCP transiently increased intracellular BDNF but decreased Trk receptor activation and downstream signaling.
• Synaptic sites and protein expression decreased 48h post-PCP without affecting cell viability.
• PCP diminished glutamatergic neurotransmission and suppressed BDNF secretion.
• Exogenous BDNF application restored Trk signaling and synaptic protein levels.

Conclusions:

• Impaired BDNF secretion and subsequent Trk signaling reduction contribute to PCP-induced synaptic loss.
• BDNF dysfunction is a potential mechanism for schizophrenia-like behaviors induced by PCP.
• Targeting BDNF pathways may offer therapeutic strategies for PCP-related neurological disorders.