PLCβ4 driven by cadmium-exposure during gestation and lactation contributes to cognitive deficits by suppressing PIP2/PLCγ1/CREB/BDNF signaling pathway in male offspring

Abstract

The fetus and infants are particularly vulnerable to Cadmium (Cd) due to the immaturity of the blood-brain barrier. In utero and early life exposure to Cd is associated with cognitive deficits. Although such exposure has attracted widespread attention, its gender-specificity remains controversial, and there are no reports disclosing the underlying mechanism of gender‑specific neurotoxicity. We extensively evaluated the learning and cognitive functions and synaptic plasticity of male and female rats exposed to maternal Cd. Maternal Cd exposure induced learning and memory deficits in male offspring rats, but not in female offspring rats. PLCβ4 was identified as a critical protein, which might be related to the gender‑specific cognitive deficits in male rats. The up-regulated PLCβ4 competed with PLCγ1 to bind to PIP2, which counteracted the hydrolysis of PIP2 by PLCγ1. The decreased activation of PLCγ1 inhibited the phosphorylation of CREB to reduce BDNF transcription, which consequently resulted in the damage of hippocampal neurons and cognitive deficiency. Moreover, the low level of BDNF promoted AEP activation to induce Aβ deposition in the hippocampus. These findings highlight that PLCβ4 might be a potential target for the therapy of learning and cognitive deficits caused by Cd exposure in early life.