Pharmaceuticals
A Novel Opto-Genetic Tool for Light Activated Synaptic Silencing (No. T4-2046)

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Overview

Defects in neurotransmitters are associated with several neurological diseases such as Parkinson’s disease, epilepsy, and psychiatric disorders. Optogenetics is a technology based on light-sensitive proteins for optical control of cellular processes. It is a powerful research tool for dissecting neuronal circuits and can potentially be used for developing treatments for neurological disorders. Prof. Ofer Yizhar and his team developed a light-sensitive protein that is efficiently expressed in mammalian neurons and suppresses neurotransmitter release in rodent hippocampal and cortical neurons. This can be used to develop new treatments for neurological diseases.

Background and Unmet Need

Several neurological disorders result from over/reduced excitation or excretion. These include Parkinson’s disease, essential tremor, epilepsy, and psychiatric disorders.

is a technology based on introducing light-sensitive proteins to cells to obtain optical control on the cellular process of gain or loss of function of specific events. Although optogenetics allows robust and spatiotemporally-precise excitation of long-range projecting axons, their silencing with the existing tools is much less efficient. Optogenetic silencing can be a powerful tool for dissecting neuronal circuits to treat neurological disorders resulting from over-excitation. It can also be a very powerful research tool for dissecting neuronal circuits and understanding the contribution of defined neuronal populations to behavioral processes. Therefore, there is an unmet need to develop an efficient method for optogenetic silencing.

The Solution

Prof. Ofer Yizhar and his team developed an optimized bistable type II opsin that efficiently and specifically recruits the Gi/o signaling cascade, resulting in suppression of synaptic neurotransmitter release in rodent hippocampal and cortical neurons.

Technology Essence

The team generated an optimized polypeptide based on a mosquito-derived homolog of the mammalian encephalopsin/panopsin protein (OPN3), which is fused to a heterologous ER export signal and/or membrane trafficking signal. The enhanced OPN3 (eOPN3) is a bistable opsin with reduced photobleaching and prolonged activity, better membrane targeting, and improved expression in long-range axons. Its exposure to light results in efficient and specific recruitment of the Gi/o signaling cascade, which inhibits neurotransmitter release (Figure 1). Therefore, eOPN3 is a robust and broadly applicable optogenetic tool for the inhibition of synaptic neurotransmission.

Figure 1. Schematic diagram depicting the mechanism through which Gi/o signaling reduces the synaptic vesicle release probability. An activated GPCR leads to inhibition of voltage-gated calcium channels and reduced cAMP levels, both leading directly (solid arrow) and indirectly (dotted arrow) to a reduction of calcium-dependent vesicle release.

 

Applications and Advantages
  • A method that can be utilized to treat a variety of neurological disorders and diseases
  • An ontogenetic tool for potent silencing of presynaptic activity with high spatiotemporal precision
  • Stable and reversible
  • A powerful neurobiological research tool
Development Status

The team developed the mosquito-derived optimized polypeptide,demonstrated it can be expressed on membranes of mammalian hippocampal neurons and, most importantly, in distal axonal presynaptic terminals. They further demonstrated that the modified opsins activated the Gi/0 pathway in neurons in response to light, suppressing presynaptic release. Furthermore, in vivo expression of the modified polypeptide mediated suppression of auditory afferents to the amygdala in mice, leading to an impaired recall of auditory-cued fear.

Patent Status: 
PCT Published: Publication Number: WO2020/188572
Prof Ofer Yizhar

Ofer Yizhar

Faculty of Biology
Neurobiology
All projects (1)
Contact for more information

Dr. Jacob Fierer

Director of Business Development, Life Science

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