Stress and trauma: BDNF control of dendritic-spine formation and regression

Abstract

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.

Keywords: BDNF; BDNF receptor; CaMK2; CaMKK; D2; Dendrite; ERK; EphB; ErbB2; ErbB4; G-protein; GKAP; Gp; HOMER; IP3; LIM kinase, phosphorylates ADF/cofilin; LIMK; N-methyl-d-aspartate; NMDA; NR1; NR2A, NR2B, subunits of the NMDA receptor; NRG-1; PAK; PDZ; PLCb; PP1; PSD-95; PTSD; RAC; RAS; ROCK; Rho GEF; Rho-GTPase; Rho-associated kinase; Rho-family GTPases, a subgroup of the superfamily of GTPases; RhoA; SFK; SHANK; Spines; Synapse; Trauma; TrkB; WASP; Wiskott Aldrich syndrome protein that triggers actin polymerization via Arp 2/3 complex; actin regulatory molecule; bPIX; brain derived neurotrophic factor; calcium calmodulin-dependent kinase 2; calcium calmodulin-dependent protein kinase kinase; cofilin; dopamine D2 receptor; downstream effector of RAC (sometimes called P21-activated kinase); ephrin receptor; extracellular signal-regulated kinases; guanine nucleotide exchange factor for RAC (GEF); guanylate kinase-associated protein; inositol triphosphate; kalirin; neuregulin 1; pCREB; phosphorylated cyclic AMP response element-binding protein; plexin A; postsynaptic density 95, a scaffolding protein; profilin; protein domain; protein lipase Cb; protein phosphatase 1; receptor for Sema 3A; receptors for neuregulin; scaffolding molecule; scaffolding protein; sema 3A; semaphorin 3A; severs and depolymerizes ADPactin; src family kinase.