Molecular correlates of impaired prefrontal plasticity in response to chronic stress.
Disturbed adaptations at the molecular and cellular levels following stress could represent compromised neural plasticity that contributes to the pathophysiology of stress-induced disorders. Evidence illustrates atrophy and cell death of stress-vulnerable neurones in the prefrontal cortex. Reduced plasticity may be realized through the destabilized function of selective proteins involved in organizing the neuronal skeleton and translating neurotrophic signals. To elucidate the mechanisms underlying these effects, rats were exposed to chronic footshock stress. Patterns of c-fos, phospho-extracellular-regulated protein kinases 1/2 (ERK1/2), calcineurin and phospho-cyclic-AMP response-element binding protein (CREB) expression were subsequently investigated. The results indicate chronic stress-induced impairments in prefrontal and cingulate signal transduction cascades underlying neuronal plasticity. The medial prefrontal cortex, demonstrated functional hyperactivity and dendritic phospho-ERK1/2 hyperphosphorylation, while reduced c-fos and calcineurin immunoreactivity occurred in the cingulate cortex. Significantly reduced phospho-CREB expression in both cortical regions, considering its implication in brain-derived neurotrophic factor (BDNF) transcription, suggests reduced synaptic plasticity. This data confirms the damaging effect of stress on cortical activity, on a molecular level. Due to the association of these markers in the regulation of BDNF signalling, these findings suggest a central role for intracellular neurotrophin transduction members in the pathways underlying cellular actions of stress in the brain.
Kuipers
S D
SD
Department of Psychiatry, Division of Biological Psychiatry, Academic Hospital Groningen, Groningen, The Netherlands. s.d.kuipers@acggn.azg.nl
Trentani
A
A
Den Boer
J A
JA
Ter Horst
G J
GJ
D000818:Animals; D001835:Body Weight; D019703:Calcineurin / Q000378:metabolism; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004597:Electroshock; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009473:Neuronal Plasticity; D009490:Neurosecretory Systems / Q000503:physiopathology; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000166:cytology / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000503:physiopathology*
D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin