AMPAZETA

Regulation of AMPA type of glutamate receptor surface diffusion by Protein Kinase ζ

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'In recent years significant progress has been made into deciphering the initial triggering mechanisms responsible for the induction of synaptic strengthening. Contrarily, very few studies address the question as to which cellular processes are responsible for the maintenance of LTP. Recently, the protein kinase M zeta (PKMζ, an atypical protein kinase C) has taken center stage in the field of synaptic plasticity due to its unique role in the maintenance of LTP. Among some of the most crucial observations are: 1) the increased in PKMζ mRNA level following LTP5, 2) Its protein product is constitutively active, 3) postsynaptic perfusion of PKMζ alone increases synaptic strength, 4) it is necessary and sufficient for the maintenance of LTP. Furthermore, its inhibition reverses pre-established LTP and most importantly erases memories. Therefore this protein merits a primary role in the maintenance of memory traces. Although PKMζ activity is crucial for the persistence of LTP however little is known about its precise cellular and molecular mechanisms of action. Recent evidence point to its role in the rapid redistribution of preexisting surface receptors on the plasma membrane. For example, pharmacologically blocking postsynaptic exocytosis with Botulinum toxin B fails to disrupt PKMζ-induced synaptic potentiation. Meanwhile the same manipulation leads to rapid and persistent rundown of synaptic transmission. Provided that blocking exocytosis is not involved in the PKMζ-mediated effects on synaptic transmission leads me to hypothesize that PKMζ must regulates surface diffusion of AMPARs either by trapping at the postsynaptic density or reshuffling of AMPARs from extrasynaptic to synaptic sites. In this proposal I will test this using a combination of high resolution imaging techniques, molecular biology and electrophysiology.'

Introduzione (Teaser)

Neurodegeneration is associated with deterioration in synapses and transmission of signals. Delineating the detailed mechanisms by which synapses form and function is central to designing targeted therapies for such diseases.

Descrizione progetto (Article)

In recent years, significant progress has been made in understanding how signal transmission between neurons can increase in strength. Known as long term potentiation (LTP), this phenomenon has received much attention as a potential therapy for various neurodegenerative disorders.

During LTP, strong activation of the N-methyl D-aspartate receptors on a presynaptic neuron leads to a cascade of events. These events culminate in an increase in glutamate AMPA receptors in the post-synaptic neuron. This in turns increases the release of neurotransmitters and prolongs the transmission of the signal.

Although considerable work has been performed on the mechanisms responsible for synaptic strengthening, very few studies address which mechanisms are responsible for maintaining LTP. With this in mind, scientists on the EU-funded 'Regulation of AMPA type of glutamate receptor surface diffusion by protein kinase' (AMPAZETA) project wished to study the molecular events which regulate excitatory synapses in the hippocampus.

Two proteins, namely protein kinase Mzeta (PKMZ) and Pin1 were recently found to be essential for LTP in hippocampal synapses. AMPAZETA researchers aimed to further elucidate the molecular mechanism by which Pin1 exerts its impact. In this context, they combined single-molecule imaging with molecular biology and single cell electrophysiology techniques.

The project's experimental outline encompassed assays to determine the impact of Pin1 on AMPA receptor surface diffusion, dendritic spine morphology, and postsynaptic density protein 95 levels. Inhibition of Pin1 affected the aforementioned processes, rendering it a potential target for manipulating excitatory synapse formation, maintenance and synaptic plasticity.

Pin1 plays a key role in age-dependent neurodegeneration and regulates the processing of amyloid precursor protein in Alzheimer's disease. The work by the AMPAZETA initiative improves our understanding of the molecular mechanisms that regulate synapse formation and LTP under physiological conditions. This information could lead to the development of new targets to reverse or ameliorate the effects of this neurodegenerative disorder.