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Understanding inhibitory dynamics in healthy and epileptic brain circuits

Discern inhibitory circuit motifs that control excitatory neuronal firing

Improve brain circuit function by inhibitory neuromodulation

Decipher lipid molecular messenger systems that regulate neurotransmission

Multimodal recording and precise manipulation of neural activity in live animals

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Mission statement

In the cerebral cortex, while glutamatergic excitatory projection neurons constitute the backbone of the circuit, GABAergic inhibitory interneurons are critical in regulating and synchronizing network activity. Impaired inhibition has been implicated in the mechanism of common brain disorders, including epilepsy. Nationwide, over three million people live with epilepsy. Current treatment options (including medication and surgical resection) leave more than one third of people with epilepsy without efficient seizure control. For several epilepsy disorders, including developmental epilepsies, there are no effective treatments.

The brain’s innate GABAergic inhibitory system is a prime target for developing novel, effective and disease modifying treatments for epilepsy and for related disorders with brain hyperexcitability. Each excitatory cell is inhibited by multiple distinct types of local circuit interneurons, the precise roles of whose in shaping normal and pathological circuit dynamics are still not known. Our immediate goal is to identify optimal targets for neuromodulatory intervention and develop cell type-specific strategies for inhibiting epilepsy.

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GABAergic inhibitory interneurons

GABA is the most important inhibitory neurotransmitter in the central nervous system, utilized by over twenty highly specialized and evolutionarily conserved types of neuron in the cerebral cortex alone. As opposed to glutamatergic neurons that give rise to excitatory projections to connect brain regions, cortical GABAergic cells are typically local circuit interneurons. The strategic positioning of inhibitory synapses is remarkably cell type-specific, and as a result each interneuron type can control unique aspects of the neural circuit by inhibiting specific synaptic pathways or regulating how and when other neurons can fire. Therefore, interneurons are highly specific targets for modulating brain function. Today, tools are becoming increasingly available for genetically targeted, in vivo, large scale, cell type-specific recording and intervention. We are particularly interested in perisomatic inhibition by basket cells, which are strategically positioned to regulate pyramidal cell spiking.


Pathological hyperexcitability

Neuronal hyperexcitability is hallmark of brain disorders. In epilepsy, excessive neural activity causes overt seizures when spreading to brain regions that control movement. However, even when seizures are not detected, similar pathological activity patterns are brewing, interfering with the ability of brain circuits to carry out their important computations. The same cells and circuits that perform these computations are also responsible for generating and spreading seizure activity. Therefore, impaired regulation of neural excitability causes both seizures and impaired cognitive function. To treat epilepsy, we need to inhibit seizures without hindering cognition. Fine-tuning the inhibitory circuits that control excitatory neuronal firing can be a powerful way to obtain this effect, and we are working on enabling neuromodulatory intervention strategies that target specific inhibitory circuit elements.


Cannabinoid control of inhibition

Cannabinoids are powerful antiepileptics, but their therapeutic potential has not been fully harnessed, due to their complex effects and side effects. The CB1 cannabinoid receptor is the most abundant G-protein coupled receptor in the brain, and can dampen synaptic transmission to silence overly active circuits. However, CB1 is found at the highest levels at inhibitory synapses. The brain’s internal endocannabinoid system can turn off inhibition by activating cannabinoid receptors. Therefore, it is likley that cannabinoids also contribute to epilepsy by suppressing inhibition. Due to the unique lipid nature of endocannabinoid messengers, the precise physiological role and molecular mechanisms of this signaling pathway are still not understood. We use innovative molecular probes and imaging methods to visualize endocannabinoid signals in the healthy and epileptic brain.


Innovative approaches

Key approaches: functional in vivo multiphoton imaging | anatomy using fluorescent confocal and superresolution microscopy | seizure detection and closed-loop intervention using optogenetics | electrophisyology

We combine advanced optical microscopy, electrophysiology and automated behavioral recording for the integrated analysis of neuronal function on the molecular, cellular and circuit levels. We constantly develop instrumentation and write analysis code to allow multimodal, multiscale experiments in behaving animals. We use cell type-specific labeling strategies and always perform rigorous and thorough anatomical characterization of the studied circuits to ground our observations in the bigger picture of cortical cell types. We are committed to publicly sharing data and code to increase the impact of our research.

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