Impaired stress-induced regulation of brain derived neurotrophic factor expression in hippocampus of glucocorticoid receptor impaired mice: Model of depression

Objective: The gene codifying for the neurotrophin Brain Derived Nurotrophic
Factor (BDNF) is a stress-responsive gene and alteration in its expression may
be important in producing some of the pathophysiological effects of stress in
the hippocampus as seen in stress-related pathologies like depression. While the
effects of stress procedures on the regulation of BDNF expression was widely
investigated in hippocampus of healthy control animals, the stress-induced effects
on BDNF hippocampal expression in “pathological” condition are still lacking.
In order to deepen our knowledge in the understanding of the effects of an acute
stressful procedure on molecular targets of synaptic plasticity we used transgenic
mice with impaired glucocorticoid receptor (GR-i) expression that represent an
animal model of depression. The hypothesis was tested that a single period of
restraint stress (6 hours) affects BDNF mRNA expression in the hippocampus
of GR-i mice differently than in wild-type (WT) mice.
Methods: Using real time RT-PCR we evaluated the effects of a 6 hours acute
stress on the levels of BDNF coding exon VIII and the activity regulated BDNF
exon IV mRNA. In the WT and in the GR-i animals, the hippocampal levels of
the two BDNF exons, immediately after the stress ended, were significantly lower
in stressed animals with the respect to respective control unstressed animals.
However, for the BDNF exon IV mRNA the reduction is most pronounced inWT animals and two-way ANOVA followed by Bonferroni posttest revealed a
significant interaction between stress response and genotype at the level of BDNF
exon IV mRNA expression.
Results: The BDNF gene is a very complex gene regulated by a wide array of
stimuli and signalling pathways. An electophoresis mobility shift assay (EMSA)
was used to study DNA-binding activity of two transcription factors with an
important role in controlling synaptic plasticity most likely trough an involvement
BDNF: the cAMP responsive element binding (CREB) protein and the nuclear
factor kB (Nf-kB). Taken together, our results show a different binding activity
of these transcription factors in GR-i mice with respect to WT mice following
acute stressful conditions.
Conclusion: The identification of the molecular mechanisms activated by
stress in GR-i mice model of depression may contribute to the development
of new strategies that reducing neuron vulnerability to stress and prevent
neurophatologocal alteration in the hippocampus.