A Novel Role for γ-Secretase: Selective Regulation of Spontaneous Neurotransmitter Release from Hippocampal Neurons

Abstract

With a multitude of substrates, ␥-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of ␥-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of ␥-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 ␥-secretase activity. Treatment of WT neuronal cultures with ␥-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 ␥-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.

Presenilin-1/γ-Secretase Controls Glutamate Release, Tyrosine Phosphorylation, and Surface Expression of N-Methyl-d-aspartate Receptor (NMDAR) Subunit GluN2B

“…Thus, we conclude that increased glutamate concentration in conditioned media from PS1 null neurons is due to enhanced release of glutamate rather than decreased uptake and degradation of the neurotransmitter. This conclusion is in agreement with recent data that neurons lacking PS1 show increased frequency of spontaneous miniature excitatory synaptic currents, suggesting enhanced neurotransmitter release (34).…”

Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex

“…Release of Aβ by glutamatergic synapses is also indicated by the finding that activation of group II metabotrophic glutamate receptors (mGluRs) triggered secretase activity and synaptic Aβ release in TgCRND8 mice (Kim et al, 2010). Glutamate as well as Aβ release may be affected; for example, age-related reduction in stimulated glutamate release has been observed in APP/PS1 transgenic mice (Minkeviciene et al, 2008); moreover, spontaneous excitatory release may also be affected in AD (Pratt et al, 2011). Glutamatergic signaling and function is also regulated by interactions of receptors like NR2B with post-synaptic scaffolding proteins, which may ultimately enhance presynaptic glutamate release (Proctor et al, 2011).…”

The very many faces of presenilins and the γ-secretase complex

“…PS was shown to be involved in γ-secretase-dependent processing of nectin 1 and 3, adhesion molecules involved in establishing cell–cell adherent junctions at synapses (Kim et al 2011). Moreover, there are some indications that γ-secretase might be essential for the regulation of neurotransmitter release (Pratt et al 2011), although the underlying mechanism — direct involvement or regulation of calcium homeostasis — is still not fully defined (Zhang et al 2009; Pratt et al 2011). …”