The effects of lysosomal Ca2+ release on membrane depolarisation and synaptic plasticity in hippocampus

• Main Author: Foster, Willam
• Other Authors: Emptage, Nigel ; Galione, Antony
• Published: University of Oxford 2017
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.735900

Intracellular Ca²⁺ signalling is essential for the control of almost every physiological process, from muscular contraction to synaptic transmission. Intracellular Ca²⁺ signals can be generated from both extracellular or intracellular Ca²⁺ stores. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous and important Ca²⁺ mobilising second messenger. NAADP signalling causes Ca²⁺ release from intracellular acidic Ca²⁺ stores. The functional roles of NAADP signalling and acidic store Ca²⁺ release in the central nervous system are relatively unknown Brailoiu et al. (2009b) showed that NAADP signalling enhances membrane excitability in neurons of the medulla, Padamsey and Emptage (2011) (Unpublished) find similar effects in pyramidal neurons of the hippocampus. I used pharmacological manipulations in combination with electrophysiological techniques and dendritic Ca²⁺ imaging to explore the effect of NAADP/acidic store signalling on membrane excitability and synaptic plasticity in pyramidal neurons of the hippocampus. I began by using a membrane permeable form of NAADP (NAADP-AM) to show NAADP/acidic store Ca²⁺ signalling caused membrane depolarisation. I also showed, with intracellular dialysis of Ca²⁺ mobilising second messengers, NAADP is unique in its ability to directly cause membrane depolarisation. I then identified glutamate, acting via metabotropic glutamate receptor 1 (mGluR1), as an endogenous stimulus that causes NAADP-mediated Ca²⁺ release and depolarisation. I next elucidated the signalling pathway responsible for mGluR1/NAADP-mediated depolarisation and showed the requirement of acidic store Ca²⁺ release, and subsequent amplification of this Ca²⁺ via ryanodine receptors by Ca²⁺-induced Ca²⁺ release. The resulting Ca²⁺ signal caused inhibition of small conductance K+ channels (SK channels) and membrane depolarisation. SK channels are described to facilitate the induction of plasticity in hippocampal synapses by modulation of GluN Ca²⁺ entry (Ngo-Anh et al., 2005). Finally, I show that the induction of mGluR1-dependent long-term potentiation requires inhibition of the SK channels via NAADP/acidic store Ca²⁺ signalling. Group 1 mGluRs are implicated in the pathogenesis of neurodevelopmental disorders such as fragile X syndrome. My findings may identify new targets for the treatment of such diseases.