Abstract
Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor—NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-γ1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission.
Highlights
Studies in both humans and animal, have shown that prenatal cocaine exposure can negatively affect attention, motor, and language skills, as well as associative and discrimination learning, all of which involve excitatory synapses [1,2,3,4]
Total expression of brain-derived neurotrophic factor (BDNF), proBDNF, full length tyrosine receptor kinase B (TrkB) (145-KDa) and truncated TrkB (95-KDa), p75NTR, N-Methyl-D-Aspartate receptor (NMDAR)-NR1 as well as the constituents of the TrkB signaling cascade including N-Shc and shc, Akt1 and ERK2 were determined by Western blotting in the tissue lysates of prefrontal cortex (PFCX) and hippocampi from 2 male and 2 female prenatal saline-treated (n = 4) and cocaine-exposed (n = 4) P21 rats (Fig 1)
Incubation of either hippocampal or PFCX slices from 2 male and 2 female prenatal saline-treated (n = 4) and cocaine-exposed (n = 4) P21 rats with 50–200 ng/ml of BDNF for 30 min had no discernible effects on expression levels of the 145-KDa or 95-KDa TrkB or p75NTR (Fig 2)
Summary
Studies in both humans and animal, have shown that prenatal cocaine exposure can negatively affect attention, motor, and language skills, as well as associative and discrimination learning, all of which involve excitatory synapses [1,2,3,4]. There is evidence indicating prenatal cocaine exposure leads to increased spine density in the cortical and subcortical regions [7] as well as hypertrophic dendritic outgrowth with atypical, tortuous dendritic profile [8]. The latter change in dendritic structure has been attributed to uncoupling of the dopamine D1 receptor from its associated Gs/olf protein, BDNF-TrkB signaling is one of the prominent upstream modulators. Prenatal Cocaine Exposure and BDNF-TrkB Upregulation of the glutamatergic function and dendritic health in brain areas such as neocortex and hippocampus [9,10,11]. It is highly conceivable the defects in glutamatergic neurotransmission and abnormal dendritic morphology found in prenatal cocaine exposed brains are partly caused by altered BDNF-TrkB signaling
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