Abstract
Growth differentiation factor-15 (GDF-15) has been implicated in ischemic brain injury and synapse development, but its involvement in modulating neuronal excitability and synaptic transmission remain poorly understood. In this study, we investigated the effects of GDF-15 on non-evoked miniature excitatory post-synaptic currents (mEPSCs) and neurotransmitter release in the medial prefrontal cortex (mPFC) in mice. Incubation of mPFC slices with GDF-15 for 60 min significantly increased the frequency of mEPSCs without effect on their amplitude. GDF-15 also significantly elevated presynaptic glutamate release, as shown by HPLC. These effects were blocked by dual TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII) antagonists, but not by a TβRI antagonist alone. Meanwhile, GDF-15 enhanced pERK level, and inhibition of MAPK/ERK activity attenuated the GDF-15-induced increases in mEPSC and glutamate release. Blocking T-type calcium channels reduced the GDF-15 induced up-regulation of synaptic transmission. Membrane-protein extraction and use of an intracellular protein-transport inhibitor showed that GDF-15 promoted CaV3.1 and CaV3.3 α-subunit expression by trafficking to the membrane. These results confirm previous findings in cerebellar granule neurons, in which GDF-15 induces its neurobiological effects via TβRII and activation of the ERK pathway, providing novel insights into the mechanism of GDF-15 function in cortical neurons.
Highlights
Growth differentiation factor-15 (GDF-15) has been implicated in ischemic brain injury and synapse development, but its involvement in modulating neuronal excitability and synaptic transmission remain poorly understood
We evaluated the effects of GDF-15 on cortical neurons in slices of mouse medial prefrontal cortex and recorded miniature excitatory post-synaptic currents and T-type calcium channel currents (IT-type VGCC), while simultaneously measuring neurotransmitter glutamate release and membrane Ca2+ channel protein expression
After incubation with GDF-15 (30 ng/mL) for 60 and 90 min, miniature excitatory post-synaptic currents (mEPSCs) frequencies increased by 34.8% and 35.7%, respectively (Fig. 1B)
Summary
Growth differentiation factor-15 (GDF-15) has been implicated in ischemic brain injury and synapse development, but its involvement in modulating neuronal excitability and synaptic transmission remain poorly understood. We recently demonstrated that GDF-15 increased the delayed rectifier outward K+ current and expression of its main component, KV2.1 α-subunit, by Src kinase activation via TβRII in rat granule neurons (CGNs)[13] These data provided the first evidence that modulation of K+ channel expression and the downstream signaling pathways by GDF-15 was receptor- and non-Smad-dependent-pathway associated. We evaluated the effects of GDF-15 on cortical neurons in slices of mouse medial prefrontal cortex (mPFC) and recorded miniature excitatory post-synaptic currents (mEPSCs) and T-type calcium channel currents (IT-type VGCC), while simultaneously measuring neurotransmitter glutamate release and membrane Ca2+ channel protein expression. We determined if the same signaling pathways and TβRII receptor previously identified in CGNs were activated by GDF-15 in mPFC neurons under these conditions
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