2012PatelSGPhD.pdf (13.66 MB)
Characterization of Amygdalar Fkbp5 Role in Stress-Induced Anxiety-Like Behaviour
thesisposted on 2013-01-11, 11:51 authored by Satyam Gunvantbhai Patel
The physiological response to excessively strong aversive stimuli – the stress response – is relatively maladaptive and leads to various psychopathologies such as anxiety disorders only in a minority of individuals. Our lab has previously shown that severe acute restraint stress heightens anxiety-like behaviour in wild-type but not in the extracellular serine protease, neuropsin, deficient mice. Dissecting molecular changes underlying genotypic differences, our microarray and qRT-PCR approaches revealed that the stress-induced upregulation of glucocorticoid receptor (GR) co-chaperone, Fkbp5, expression in the amygdala is significantly attenuated in neuropsin-/- mice compared to the wild-type mice and attenuated expression can be restored by bilateral intraamygdala injection of recombinant neuropsin. Further, blocking neuropsin cleavage of EphB2 with anti-EphB2 antibody suppressed only neuropsinmediated but not corticosterone-driven upregulation of Fkbp5 expression in primary amygdala cultures unraveling novel neuropsin-dependent mechanism acting in synergy with the well characterized corticosterone pathway to mediate the robust stress-effect on Fkbp5 expression. Importantly, wild-type mice lacking amygdala specific Fkbp5 exhibit stress protective phenotype in unconditioned anxiety tests and unimpaired learning and memory in fear conditioning paradigm. Proteomic analysis using subcellular fractionation revealed that stress triggers nuclear translocation of constitutively cytoplasmic FKBP51 in the amygdala. Nuclear FKBP51, in dexamethasone treated N2a cells, co-purifies with linker histone H1 implying at possible FKBP51 involvement in posttranslational modification of histone H1 to control gene expression necessary for maladaptive neuronal plasticity underlying altered behavioural outcomes. Therefore, this study characterizes and concludes an indispensable role of amygdalar Fkbp5 in stressful episodes developing into anxiety disorders.
Date of award2012-12-01
Awarding institutionUniversity of Leicester