COMPLEMENT AND GLUTAMATERGIC NEUROTRANSMISSION: A PRESYNAPTIC POINT OF VIEW
- Guendalina Olivero, Italy
Abstract
Background and Aims
In the central nervous system (CNS) complement has functions that go beyond the immune surveillance. It's involved in the control of the synaptic plasticity, dictating neurogenesis and synaptic modelling, but the molecular mechanisms, particularly those occurring presynaptically, are so far poorly investigated. Owing to shed light on these aspects, we investigated i) whether complement can affect the release of neurotransmitters from presynaptic nerve endings (synaptosomes) and ii) if antigen-antibody complexes at the outer side of synaptosomal plasmamembranes can trigger additional complement-induced responses.
Methods
Mouse synaptosomes were exposed to complement in superfusion and the release of glutamate, GABA, noradrenaline and acetylcholine quantified. When indicated, synaptosomes were preincubated with antibodies recognizing the outer sequence of NMDA and AMPA receptors subunits.
Results
Complement released glutamate in a dilution-dependent, carrier-mediated manner from mouse cortical, hippocampal, cerebellar and spinal cord synaptosomes. Complement releasing activity was restricted to glutamatergic terminals since the release of GABA, noradrenaline and acetylcholine was not affected. The incubation of synaptosomes with antibodies recognizing the outer sequence of the GluA2 and GluA3 AMPA receptor proteins significantly increased the complement-evoked release efficiency in a C1q-dependent fashion, while exposure to anti-GluN1 and anti-GluN2B NMDA receptor proteins antibodies reduced it. The last effect is linked to an antibody-induced internalization of NMDA receptors, unveiling a NMDA-mediated component of the complement releasing activity.
Conclusions
Our observations improve the knowledge of the complement-mediated control of glutamatergic transmission at chemical synapsis and of the molecular events underlying the cross-talk linking the immune system and the CNS.