Modulation of GABAB receptors in the insula bidirectionally affects associative memory of epilectic rats in both spatial and non-spatial operant tasks

Abstract

BackgroundStimulation of gamma-aminobutyric acid (GABA) activity through GABA receptor agonists is the basic mechanism of many anticonvulsant drugs. Nevertheless, many of these GABergic drugs have adverse cognitive effects. We previously found that GABAB receptors (GABABRs) in the insula regulate operant associative memory in healthy rats. The present study aimed at investigating the effects of GABABR modulation in the insula on operant associative memory in epileptic rats, along with the underlying mechanisms.MethodsThe lithium-pilocarpine model of temporal lobe epilepsy (TLE) was established in male Sprague–Dawley rats. A 22-gauge stainless-steel guide cannula was surgically implanted into the granular insula cortex of the epileptic rats. Baclofen (125 ng/μl, 1 μl), CGP35348 (12.5 μg/μl, 1 μl), or saline (1 μl) was slowly infused through the guide cannula. The Intellicage automated behavioral testing system was used to evaluate operant associative memory of the epileptic rats, including non-spatial operant tasks (basic nosepoke learning and skilled nosepoke learning) and spatial operant tasks (chamber position learning). The expression of the GABABR subunits GB1 and GB2 in the insula was examined by immunofluorescence and Western blotting.ResultsThe Intellicage tests demonstrated that baclofen significantly impaired basic nosepoke learning, skilled nosepoke learning and chamber position learning of the epileptic rats, while CGP35348 boosted these functions. Immunofluorescence staining revealed that GB1 and GB2 were expressed in the insula of the epileptic rats, and Western blotting analysis showed that baclofen enhanced while CGP35348 inhibited the expression of these subunits.ConclusionGABABRs in the insula bidirectionally regulate both spatial and non-spatial operant associative memory of epileptic rats. Effects of GABABRs on cognition should be taken into account when evaluating new possible treatments for people with epilepsy.

IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system

“…However, the IntelliCage software could be used to run this system without modifications, because the inputs (presence, nose-poke, licks) as well as the outputs (opening/moving doors, activating LED and delivering air-puffs) were the same, and so the adaptation work was chiefly mechanical and permitted rapid use of the rat systems. Nonetheless, it took some years until the first rat paper appeared ( Urbach et al, 2014 ), but then others followed, 13 over the past 5 years, proving that the mouse IntelliCage system could be adapted successfully to larger rodent species ( Yang et al, 2017 ; Oliveros et al, 2018 ; Pelsőczi et al, 2020 ; Zheng et al, 2020 ; Cao et al, 2021 ; Esmaeili et al, 2022 ; Pham et al, 2022 ; Shishelova et al, 2022 ; Xiao et al, 2022 ; Li et al, 2023a , b ; Pupikina and Sitnikova, 2023 ; Wu et al, 2023 ).…”