Comparative Assessment of TSPO Modulators on Electroencephalogram Activity and Exploratory Behavior

Abstract

Network communication in the CNS relies upon multiple neuronal and glial signaling pathways. In addition to synaptic transmission, other organelles such as mitochondria play roles in cellular signaling. One highly conserved mitochondrial signaling mechanism involves the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane. Originally, TSPO was identified as a binding site for benzodiazepines in the periphery. It was later discovered that TSPO is found in mitochondria, including in CNS cells. TSPO is implicated in multiple cellular processes, including the translocation of cholesterol and steroidogenesis, porphyrin transport, cellular responses to stress, inflammation, and tumor progression. Yet the impacts of modulating TSPO signaling on network activity and behavioral performance have not been characterized. In the present study, we assessed the effects of TSPO modulators PK11195, Ro5-4864, and XBD-173 via electroencephalography (EEG) and the open field test (OFT) at low to moderate doses. Cortical EEG recordings revealed increased power in the δ and θ frequency bands after administration of each of the three modulators, as well as compound- and dose-specific changes in α and γ. Behaviorally, these compounds reduced locomotor activity in the OFT in a dose-dependent manner, with XBD-173 having the subtlest behavioral effects while still strongly modulating the EEG. These findings indicate that TSPO modulators, despite their diversity, exert similar effects on the EEG while displaying a range of sedative/hypnotic effects at moderate to high doses. These findings bring us one step closer to understanding the functions of TSPO in the brain and as a target in CNS disease.

Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

“…Second, the dose of XBD173 (5 mg/kg) used by Shi et al, [ 26 ], as well as the duration (consecutive days), varies considerably from our study (1 mg/kg every alternate day). In line with these hypotheses, a recent study showed that XBD173 at a higher dosage (5 mg/kg) compared to the lower dosage (1 mg/kg) affects the mouse locomotory and exploratory behavior and also decreases the gamma power in EEG recordings [ 27 ]. Given the importance of gamma power in maintaining working memory-related processes, one could speculate that a decrease in gamma power resulting from a higher dosage of XBD173 impairs cognitive functions.…”

“…However, the recent findings from Shi et al, suggest that diazepam via TSPO alters synaptic plasticity [ 26 ]. Additionally, both the ligands Ro5-4864 and PK11195 have been shown to alter the locomotor and exploratory behavior as well as affect band-specific changes in EEG [ 27 ]. As such, it remains to be resolved whether TSPO ligands exert beneficial or detrimental effects on neuroplasticity.…”