| Brain-derived neurotrophic factor (BDNF) upregulates glutamatergic transmission and N-Methyl-D-Aspartate receptor (NMDAR) function through the activation of tropomyosin-related kinase receptor type B (TrkB). Conversely, NMDAR activation influences BDNF release. Because prenatal cocaine exposure can markedly alter glutamatergic transmission and NMDAR activation, we hypothesized that a dysregulation of the glutamatergic system following prenatal cocaine exposure could result in long-lasting alteration of TrkB signaling, thereby influencing the interaction between TrkB and glutamatergic NMDARs. In agreement with this hypothesis, we found that activated (i.e. tyrosine-phosphorylated) TrkB (pY-TrkB) levels in response to exogenous BDNF were increased in both the prefrontal cortex and hippocampus of 21-day-old rats that were exposed prenatally to cocaine. This cocaine-induced effect was corroborated by an elevated pY-TrkB-associated phospholipase, C-γ1, and adapter protein, Shc, as well as increases in downstream extracellular signal-regulated kinase 2 (ERK2) and PI3K signaling.;We report a significant decrease in the levels of BDNF released at the synapse of prenatal cocaine- exposed rats compared to control after NMDA and K+ stimulation and a marked increased affinity of receptor TrkB to its ligand BDNF. This suggests that increased activation and signaling of TrkB in prenatal cocaine- exposed rats is the result of increased affinity of TrkB to BDNF, possibly as a functional compensation for decreased levels of activity-dependent BDNF released at the synapse. Moreover, we found a decreased activity of the p75 neurotrophin receptor(p75NTR) death-inducing pathways, as assessed by p75NTR recruitment of adaptor proteins TRADD, FADD, and TRAF2/6, and corroborated by decreased downstream Janus kinase 1 (JNK1) activation, as indicated by lower JNK1 phosphorylation (p-JNK1) levels.;Our data suggest that BDNF–TrkB and BDNF–/proBDNF-p75 NTR activities are reduced following prenatal cocaine exposure due to a marked reduction in BDNF/Thrown Away proBDNF release. Given that neurotrophins and glutamate receptors interact to modulate the health and excitability of glutamatergic synapses, upregulation of BDNF–TrkB signaling and downregulation of BDNF–/proBDNF p75NTR pathways suggests a more efficient neurotrophin signaling in an attempt to reestablish synaptic homeostasis when supplies of BDNF are restored. |
