2012PatelSGPhD.pdf (13.66 MB)
Characterization of Amygdalar Fkbp5 Role in Stress-Induced Anxiety-Like Behaviour
thesis
posted on 2013-01-11, 11:51 authored by Satyam Gunvantbhai PatelThe 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.
History
Supervisor(s)
Pawlak, RobertDate of award
2012-12-01Awarding institution
University of LeicesterQualification level
- Doctoral
Qualification name
- PhD