Toll and kinase-less Trk receptors in concert drive a novel mechanism of structural synaptic plasticity.
Award Number
BB/R017034/1Status / Stage
CompletedDates
9 November 2018 -8 November 2022
Duration (calculated)
03 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£475,100.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of BirminghamPrincipal Investigator
Professor Alicia HidalgoPI Contact
a.hidalgo@bham.ac.ukPI ORCID
0000-0001-8041-5764WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 702 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/R017034/1 |
|---|---|
| Status / Stage | Completed |
| Start Date | 20181109 |
| End Date | 20221108 |
| Duration (calculated) | 03 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Birmingham |
| Funding Amount | £475,100.00 |
Abstract
The aim is to test the hypothesis that a recently discovered molecular mechanism promotes neuronal activity dependent structural plasticity, to deliver appropriate behaviour. In humans, neurotrophins (NTs) modulate synaptic and structural plasticity via the tyrosine kinase function of the receptor TrkB. Paradoxically, the most abundant TrkB isoforms in the adult human brain lack the tyrosine kinase, but their neuronal functions are unknown. Toll-Like-Receptors could also be involved in brain plasticity, but their neuronal functions remain unknown. We discovered that Drosophila neurotrophins (DNTs) bind Toll and kinase-less Trk-family receptors encoded by the kekkon (kek) genes. DNT2 is a retrograde ligand for a pre-synaptic receptor complex formed of Kek-6 and Toll-6 that together regulate neuronal number, synaptic structure and arbor growth. We suspect that they modulate synaptic function and respond to neuronal activity to mould structural changes in neurons to functional requirements. We will test this idea in the Drosophila larva by: (1) Determining the molecular mechanism of Kek-6 function. We have identified 13 candidate effectors. Using optogenetics, GCaMP calcium imaging, genetics and co-immunoprecipitations, we will validate 1- 5. (2) Cracking the Kek-Toll code. Kek-6 and Toll-6 signalling can cross-talk downstream, and using genetic epistasis analysis, confocal and expansion microscopy at the neuromuscular junction (NMJ), we will test the effect on synaptic structure. With image registration to the connectome, we will see whether different Keks and Tolls are in different motorneuron types, dentrite vs. axonal arbors, or whether they overlap. (3) We will select 2-3 Kek-Toll pairs to investigate at NMJ or dendrite. Using electrophysiology, opto- and thermo-genetics, to examine, activate and silence neurons, genetics to switch genes on or off and microscopy, we will test how these mechanisms affect activity-dependent structural plasticity and behaviour.
Aims
The aim is to test the hypothesis that a recently discovered molecular mechanism promotes neuronal activity dependent structural plasticity, to deliver appropriate behaviour.