title: Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice.
abstract: Serotonin 1A (5-HT(1A)) receptors in brain play an important role in cognitive and integrative functions, as well as emotional states. Decreased brain-derived neurotrophic factor (BDNF) expression and/or function, particularly in hippocampus, are implicated in the pathophysiology of stress-related disorders such as major depression. BDNF(+/-) mice are more vulnerable to stress than wild-type mice, exhibiting behavioural despair after mild handling stress. We examined the effect of mild handling stress on 5-HT(1A) receptor function, as measured by 8-OH-DPAT stimulated [(35)S]GTPγS binding, in BDNF(+/-) mice and mice with a forebrain-specific reduction in BDNF (embryonic BDNF inducible knockout mice). Our data show a remarkable sensitivity of hippocampal 5-HT1A receptors to mild stress and a deficiency in BDNF. Other 5-HT(1A) receptor populations, specifically in frontal cortex and dorsal raphe, were resistant to the combined detrimental effects of mild stress and reductions in BDNF expression. Decreases in hippocampal 5-HT(1A) receptor function induced by mild stress in BDNF-deficient mice were prevented by administration of the selective serotonin reuptake inhibitor fluoxetine, which increased activation of TrkB, the high affinity receptor for BDNF, in wild-type and BDNF(+/-) mice. In hippocampal cultures, BDNF increased the capacity of 5-HT(1A) receptors to activate G proteins, an effect eliminated by the knockout of TrkB, confirming TrkB activation increases 5-HT(1A) receptor function. The mechanisms underlying the sensitivity of hippocampal 5-HT(1A) receptors to mild stress and decreased BDNF expression remain to be elucidated and may have important implications for the emotional and cognitive impairments associated with stress-related mental illness.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Burke
authors.forename: Tushar
authors.initials: T
authors.lastname: Advani
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
authors.forename: Julie G
authors.initials: JG
authors.lastname: Hensler
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D044282:Receptor, Serotonin, 5-HT1A