Lasky, D. J. | Search bioRxiv

bioRxiv2024

Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway dependent AMPK activation.

Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation.

neuroscience↗

bioRxiv2022

Dual orexin antagonist DORA-22 suppressed posttraumatic seizures and enhances GABAergic inhibition in dentate granule cells

BackgroundTraumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. MethodsCD-1 mice underwent controlled cortical impact (CCI), sham craniotomy or no craniotomy. Sham and CCI groups underwent a month-long treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol). We performed week-long EEG recordings during week-1 of treatment and again at months 1, 2 and 3. Seizure analysis occurred at all-time points and sleep analysis occurred in week-1 and month-1 recordings in all groups. Subsets of animals in sleep aid-treated and untreated CCI, and sham groups were subjected to voltage clamp experiments. ResultsDORA-22 treated group had seizures at week-1 but none at months 1-3. TBI reduced amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased non-rapid eye movement sleep (NREM) in the first 4hours of lights-off whereas THIP increased REM sleep in the first 4-hours of lights-on in week-1, At month-1 both treatments reduced time in NREM during lights-off. TBI increased NREM delta power (N{Delta}) along with loss of the homeostatic overnight decline of N{Delta} in week-1 regardless of treatment. DORA-22 and THIP treatment restored N{Delta} to levels similar to no craniotomy animals at month-1. ConclusionsDORA-22 treatment suppressed posttraumatic seizures possibly due to enhanced GABAergic inhibition in dentate granule cells. DORA-22 may have therapeutic potential in suppressing PTE. Summary for Social MediaTraumatic brain injury (TBI) can result is posttraumatic epilepsy and sleep disturbances. There are no treatments to prevent these complications. We tested whether treatment with sleep aids after TBI can mitigate seizures and sleep disturbances. We found that a sleep aid DORA-22 but not THIP suppressed post traumatic seizures possibly be enhancing GABAergic inhibition in the hippocampus. Sleep analysis showed that TBI disrupts the sleep homeostatic drive and DORA treatment restored it. Findings may lead to potential disease modifying therapy for posttraumatic epilepsy.

neuroscience↗