| First Author | Pratt KG | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 3 | Pages | 899-906 |
| PubMed ID | 21248114 | Mgi Jnum | J:168562 |
| Mgi Id | MGI:4889001 | Doi | 10.1523/JNEUROSCI.4625-10.2011 |
| Citation | Pratt KG, et al. (2011) A novel role for {gamma}-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons. J Neurosci 31(3):899-906 |
| abstractText | With a multitude of substrates, gamma-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of gamma-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of gamma-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support gamma-secretase activity. Treatment of WT neuronal cultures with gamma-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for gamma-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals. |
