Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti

Abstract

Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA 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 inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana 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 povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom.

Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotionalityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.