Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti

Abstract

Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne procese značajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFAD modelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5 GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu, objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju, ekspresiju subjedinica GABAA receptora i neuroinflamaciju. Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni i netransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresije gena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusu i prefrontalnom korteksu pomoću qPCR metode. Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalno prepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenih mužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenih mužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat na kognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratila na normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki. U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećao Gabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivne simptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornih gena kod transgenih ženki i astroglioze kod transgenih mužjaka. Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efekte kod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva više studija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima sa izraženom neuroinflamacijom.

Aims: GABAergic modulation involved in cognitive processing appears to be substantially changed in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, sensorimotor function, emotionality, motivation, expression of GABAA receptor subunits and neuroinflammation. Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determined in hippocampus and prefrontal cortex by qPCR analysis. Results: PAM treatment impaired spatial learning in transgenic females, and social recognition and motor function in both transgenic and non-transgenic males and in transgenic males, respectively. NAM treatment declined social interaction and emotionality in both transgenic and non-transgenic males and transgenic males, respectively. NAM had a beneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, both treatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. In prefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2 in transgenic males. Transgenic animals have not fully displayed cognitive symptoms, while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males. Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with prominent neuroinflammation.