Biology subjects

Carrette, E.

Publications and source records attributed to Carrette, E..

3 recordsLinked to original sources

bioRxiv2024

Photopharmacological activation of adenosine A1receptor signaling suppresses seizures in a mousemodel for temporal lobe epilepsy

Up to 30% of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to uncage sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photo-uncaging of cCPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-uncaging of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-uncaging of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.

neuroscience↗

bioRxiv2024

Feedback Control of Neuronal Excitability and Epileptiform Bursting using a Photocaged Adenosine A1 Agonist

Adenosine is a potent regulator of neurotransmission and neuronal excitability through activation of Gi protein-coupled adenosine A1 receptors (A1Rs). It has gained interest as a potential anticonvulsant due to its endogenous involvement in ending ongoing seizure activity. A recently developed coumarin-caged derivative of the A1R agonist N6-cyclopentyl-adenosine (CPA), cCPA, was used for photo-uncaging of CPA with millisecond flashes of 405 nm light. At population level, CPA reduces Schaffer Collateral stimulated extracellular dendritic field potentials (FPs) in the CA1 region of the hippocampus with an ED50 of 44.1{+/-}2.8 nM and a Hill coefficient of 3. Response onset is CPA dependent and takes less than seconds, while recovery is CPA independent with a time constant of around 20 minutes. A closed-loop feedback system used the amplitude of evoked dendritic FPs to photorelease CPA and was able to control FP amplitude to user defined levels between 10% and 90% of baseline level. In the acute elevated potassium model of epilepsy raising extracellular K+ to 8.5 mM enhances neuronal excitability and induces regularly occurring epileptiform bursts, but FPs evoked with low intensity could still continuously monitor excitability without interfering with bursting. In this model the closed-loop system that controlled CPA release, was able to suppress epileptiform bursting, while maintaining an acceptable level of functional neurotransmission. Including in the control algorithm a second parameter that combined population spike amplitude and number of population spikes, enabled the system to automatically find a level of functional neurotransmission that was just below the threshold for multiple spiking and epileptiform bursting. The combination of photopharmacological adenosinergic modulation with real-time FP monitoring provides a first step towards closed-loop precision treatment for diseases related to neuronal hyperexcitability such as epilepsy.

neuroscience↗

bioRxiv2023

Modulation of locus coeruleus neurons and strong release of noradrenaline during acute hippocampal seizures in rats

The locus coeruleus (LC), a brainstem nucleus, is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the regulation of excitability and plasticity of large-scale brain networks. In this study, we assessed the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation. LC neurons were recorded in anesthetized rats using a multichannel electrophysiology probe and were identified based on electrophysiological characteristics or optogenetic tagging. The majority of LC neurons (55%) were inhibited during seizures, while only a subset of LC neurons (28%) was excited during seizures. Topographic analysis of multi-unit activity showed anatomical separation of neurons that were excited and inhibited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRABNE2m, in combination with fiber photometry in both anesthetized and awake rats. Our results indicate that acute electrically evoked hippocampal seizures are associated with strong changes in LC unit activity and strong and consistent time-locked release of noradrenaline. Understanding the role of mass release of noradrenaline during hippocampal seizures is likely to be important to understand seizure pathophysiology.

neuroscience↗