SYNAPTIC ER

Understanding mechanisms regulating endoplasmic reticulum dynamics in hippocampal synaptic plasticity

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 Obiettivo del progetto (Objective)

'Dendritic spines are microdomains with dynamic distribution of ionotropic glutamate receptors and associated proteins involved in synaptic transmission. In the hippocampus, two forms of long-lasting changes in synaptic activity — long-term potentiation and long-term depression (LTD) — are thought to underlie learning and memory processes. Of the three ionotropic glutamate receptors, it is the AMPA receptor (AMPAR) that mediates the majority of fast excitatory synaptic transmissions in spines. Most AMPARs are calcium impermeable. The incorporation of AMPAR GluA2 subunit is important for this functional characteristic and this occurs before the exit from endoplasmic reticulum (ER). ER is dynamically distributed in subpopulations of hippocampal dendritic spines. These ER-containing spines can play important roles in many neuronal functions, and ER expulsion from spines is likely to affect spine signaling and plasticity. But whilst research on receptor trafficking and the associated postsynaptic protein complex has greatly advanced our understanding on LTD, the contribution of spine ER dynamics has been over-looked. In this connection, the present proposal aims to test the hypothesis that dynamic ER distribution in spines can contribute to synaptic plasticity by elucidating whether there are any common mechanisms regulating AMPAR GluA2 subunits and ER dynamics in relation to metabotropic glutamate receptor dependent LTD induction. This is a novel approach and requires combination of advanced live-cell imaging and electrophysiological recordings to study how the structural and functional plasticity in a single spine accords with the dynamic change in ER and the intracellular molecular events. It is anticipated that this research will shed insights into the physiologies and pathophysiologies of synaptic ER and contribute to a significant step forward in synaptic research.'

Introduzione (Teaser)

Deterioration of memory is a common feature of many neurological conditions, such as dementia. Understanding how memories are formed is essential to develop effective targeted therapy.

Descrizione progetto (Article)

Synaptic plasticity, the ability of the synapses to strengthen or weaken over time, involves long-lasting increase (or long-term potentiation) in signal transmission between two neurons or long-lasting decrease in synaptic strength. The number of neurotransmitter receptors located on a synapse contributes to synaptic plasticity.

Two glutamate receptors, Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors are related to long-term potentiation. The EU-funded project SYNAPTIC ER (Understanding mechanisms regulating endoplasmic reticulum dynamics in hippocampal synaptic plasticity) has found a connection between glutamate receptors and endoplasmic reticulum (ER).

During transmission, the signal travels from an axon of one neuron to the dendrite of a second neuron, receiving an input. The surface of a dendrite has dendritic spines, or small protrusions. Interestingly, some dendritic spines contain ER. These ER-containing spines are highly dynamic but the role of ER in dendritic spines has not been studied in detail.

The scientists expressed different fluorescent markers in hippocampal neuronal cultures. The markers allowed them to follow the internalisation of glutamate receptors at synapses and to visualise the ER. The imaging experiments on ER-containing and ER-lacking spines showed that there was no correlation between AMPA receptor internalisation and ER content. However the activity of the NMDA receptor was found to be responsible for changes in spine size and the associated ER dynamics. Activation of NMDA receptors promoted rapid ER expansion in growing spines.

The SYNAPTIC ER project has added to the knowledge base defining the role and mechanisms regulating spine ER dynamics in synaptic physiology. The results will help define molecular targets for developing drugs to treat neurodegenerative disorders such as Alzheimer's.