Transcranial photopharmacological modulation of excitatory-inhibitory unbalance in neurodevelopmental diseases.

Group: Nanoprobes and nanoswitches and Molecular and cellular neurobiotechnology
Group leader: Pau Gorostiza (pgorostiza@ibecbarcelona.eu) and José Antonio del Rio (jadelrio@ibecbarcelona.eu)

 

Project:

In order to understand and model how neural circuits work at the level of individual synapses, new molecular tools are required to control the activity of the different types of ion channels and receptors at high spatiotemporal precision and pharmacological selectivity. Photopharmacology allows modulating protein activity with light in the intact brain. We have recently introduced two photon pharmacology (2PP, Pittolo et al., 2019) and showed that it allows to reversibly silence specific receptor activity using spatiotemporal patterns of illumination: using photopharmacology and two-photon excitation with pulsed infrared lasers, endogenous neuroreceptors can be photoactivated at will with pharmacological selectivity and with micrometer axial resolution.

In addition to these fundamental purposes, photopharmacological neuromodulators that respond optimally to red and infrared light also offer therapeutic opportunities, because the deep penetration of these wavelengths in the brain enables non-invasively controlling neural activity, for example during epileptic seizures or neurodegeneration.

In this project, we aim to develop neuroinhibitors responding to (infra)red light and apply them to (1) understand how complex neural circuits work using 2PP of diverse receptors, and (2) restore inhibitory signalling in order to prevent pathological consequences of the excitatory-inhibitory unbalance in animal models of epilepsy, thus demonstrating a proof-of-concept of transcranial photopharmacological modulation (tPPM).

Electrical and magnetic modulation of the nervous system is clinically used to treat tremor and Parkinson’s disease, obsessive-compulsive disorder, epilepsy, major depression, migraine, and chronic pain, and provide important benefits to patients, their families, and society. Developing new technologies with enhanced spatiotemporal resolution and specificity of stimulation would have great interest both for basic and clinical research.

Job position description:

The project has both fundamental and translational sides, and a commitment to set up a practical methodology to stop epileptic seizures in vivo. For this reason, researchers of diverse disciplines can develop it and it offers a unique opportunity for training. In addition to participating in the photopharmacological design of the compounds, and to testing their efficacy in brain slices and in small animals, he/she should learn and be specialized in animal models of the relevant diseases (e.g. epilepsy), carry out electrophysiological and imaging characterization, and behavioral assays. The candidate would perform experiments independently at IBEC or in the Hospital Sant Joan de Déu (HSJD). An interesting profile would be a clinical resident interested in pursuing a career in translational medicine, or a pharmacologist with experience in research with animal models of disease, but other backgrounds can fit as well.

According to the Severo Ochoa research programme (2019-2022) of IBEC, this proposal contributes to one of the objectives of Bioengineering for Healthy Ageing (SCH2): Development of light-regulated neuroligands for sight restoration and control of epileptic seizures. (ATP2).