Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-[beta]1 in the CNS

Transforming growth factor [beta]1 (TGF-[beta]1) is a pleiotropic cytokine expressed throughout the CNS. Previous studies demonstrated that TGF-[beta]1 contributes to maintain neuronal survival, but mechanistically this effect is not well understood. We generated a CNS-specific TGF-[beta]1-deficient mouse model to investigate the functional consequences of TGF-[beta]1-deficiency in the adult mouse brain. We found that depletion of TGF-[beta]1 in the CNS resulted in a loss of the astrocyte glutamate transporter (GluT) proteins GLT-1 (EAAT2) and GLAST (EAAT1) and decreased glutamate uptake in the mouse hippocampus. Treatment with TGF-[beta]1 induced the expression of GLAST and GLT-1 in cultured astrocytes and enhanced astroglial glutamate uptake. Similar to GLT-1-deficient mice, CNS-TGF-[beta]1-deficient mice had reduced brain weight and neuronal loss in the CA1 hippocampal region. CNS-TGF-[beta]1-deficient mice showed GluN2B-dependent aberrant synaptic plasticity in the CA1 area of the hippocampus similar to the glutamate transport inhibitor DL-TBOA and these mice were highly sensitive to excitotoxic injury. In addition, hippocampal neurons from TGF-[beta]1-deficient mice had elevated GluN2B-mediated calcium signals in response to extrasynaptic glutamate receptor stimulation, whereas cells treated with TGF-[beta]1 exhibited reduced GluN2B-mediated calcium signals. In summary, our study demonstrates a previously unrecognized function of TGF-[beta]1 in the CNS to control extracellular glutamate homeostasis and GluN2B-mediated calcium responses in the mouse hippocampus. [PUBLICATION ABSTRACT]