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Synaptic mechanisms underlying neural coding in the retina during visual response

Final Report Summary - SYNAPSE TRANSMISSION (Synaptic mechanisms underlying neural coding in the retina during visual response)

• A summary description of the project objectives:

1. To study synaptic transmission in the context of the zebrafish retina
2. To develop new optical tools to perform functional imaging and investigate synaptic transmission

• A description of the work performed since the beginning of the project:

1. Molecular biology – preparing plasmid constructs for achieving expression of optical reporters and fluorescent proteins in primary hippocampal cultures and to make transgenic zebrafish
2. Imaging – perform fluorescence imaging experiments under the single-photon and two-photon illumination using primary hippocampal neuronal cultures and the zebrafish retina
3. Optogenetic experiments
4. Development of novel optical tools
5. Data analysis and programming
6. Conference presentations

• A description of the main results achieved so far:

1. We identified that synaptic terminals from one and the same bipolar cell can transmit information differently to downstream post-synaptic ganglion cells. This appears to be true for both digital and analog signal transmission from the bipolar cell terminals. Such a “multiplexed” computation broadens the repertoire of synaptic processing and computation and will be applicable to other areas of the brain. The results are being investigated further to understand the mechanisms.
2. We were able to target CatCh (a more calcium-permeable variant of channelrhodopsin) to the presynaptic membrane. With a channelrhodopsin variant more selective for calcium ions, we will achieve our goal of having a light-activable calcium channel localized to the presynaptic membrane.
3. We have developed new spectrally red-shifted optical reporters to monitor calcium signals in synaptic terminals – SyjRGECO1a
4. We have studied synaptic computation at the level of bipolar cell terminals and amacrine cell terminals in the presence and absence of Müller cells. We applied visual stimuli of varying luminance intensities and temporal contrast varying in frequency. The results (specified in the work description) provide a unique understanding that the retina can still be functional, albeit with a reduced gain, in terms of processing visual information. A manuscript from this work is under preparation.

• The expected final results and their potential impact and use (including the socio-economic impact and the wider societal implications of the project so far).

1. Our work has provided new insights into the working of synapses in the retina and also sets a framework on which newer experiments can be carried out both within and outside our laboratory.
2. Development of lasting cooperation and collaborations with other countries (e.g. the fellow has successfully carried forward collaboration with the lab of Loren Looger (Janelia Farm Research Campus, HHMI, Ashburn, Virginia, USA and initiated a collaboration with Dr. Ryan MacDonald, University of Cambridge). This achieves the goal of scientific integration and exchange of ideas within the European community and also with non-European countries.
3. The expertise obtained in optical tools, reporters of synaptic activity, and imaging has paved a way for future collaboration with Janssen Pharmaceuticals, Belgium to study synaptic pathologies for neurodegenerative diseases and design high-content screening methods using the new optical tools to develop novel treatments. This is important in terms of fostering industry-academia collaboration within the European scientific community, establishing translation research, and having a potential positive impact on health-associated issues and their economic consequences.
4. The work done so far with the support of this fellowship and the future directions it has provided, gives us the possibility to publish novel understanding of retinal synaptic circuits in high impact journals. The work has been carried out in two institutes in the UK – MRC Laboratory of Molecular Biology, Cambridge and University of Sussex; thus, it will enhance the overall European excellence and increase the visibility and competitiveness of European science across the world.
5. The work performed with the support of this fellowship has been presented in the form of a poster and was selected for a talk at a conference held at Janelia Farm Research Campus in May 2014 (‘Genetic Manipulation of Neuronal Activity III'). The scientific publications being written and that will be written based on the work performed with the support of this fellowship will be duly acknowledged.