Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling.
- 1Departments of Physiology, Pharmacology and Neuroscience, School of Medicine at CCNY, The City University of New York, New York, New York, 10031, United States of America.
- 2Department of Biology, Neuroscience Program, Graduate School of The City University of New York, New York, New York, 10061, United States of America.
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.
- PMID: 27494324; DOI:10.1371/journal.pone.0160585
Cocaine exposure during gestation has deleterious effects on excitatory synaptic activities leading to deficits in attention, motor, and language skills, as well as reduced learning capability (for review: Romano and Harvey, 1996; Bandstra et al., 2002). These impairments are corroborated by our earlier studies indicating that in utero cocaine exposure attenuates glutamatergic neurotransmission including ionotropic NMDA and AMPA receptors and metabotropic mGluR1 (Yablonsky-Alter et al., 2005; Bakshi et al., 2009, 2014). The defective excitatory glutamatergic neurotransmission resulting from prenatal cocaine exposure is linked to compensatory upregulation of BDNF-TrkB signaling (Stucky et al., 2016).
Alterations in BDNF-TrkB signaling levels during critical developmental stages can greatly affect structure and function of the brain later in life (Gao et al., 2009). By upregulating BDNF-TrkB signaling and the TrkB-NMDAR interaction, it is conceivable that prenatal cocaine exposure may cause protracted alterations of dendritic architecture, synaptic connectivity (Jones et al., 2000; Churchill et al., 2002; Frankfurt et al., 2009), and neurotransmission, especially within the glutamatergic system (Levine et al., 1995; Suen et al., 1997; Figurov et al., 1998; Bakshi et al., 2009; Lu et al., 2009).
It is well established that the pro-survival, synaptic promoting activity of BDNF-TrkB signaling is counterbalanced by the pro-apoptosis and synaptic downgrading activity mediated by p75NTR. We therefore hypothesize that in addition to increase TrkB activation prenatal cocaine exposure may also influence p75NTR-mediated signaling. An altered p75 signaling efficiency could be especially important in the overall TrkB activity because activity-dependent BDNF and pro-BDNF release is reduced in prenatal cocaine-exposed brains (Stucky et al., 2016).
P75NTR receptor can be activated by BDNF although a markedly higher BDNF level is required to trigger p75NTR signaling (Stucky et al., 2016). Here we used a high concentration (200 ng/ml) of BDNF to investigate how in utero cocaine exposure affects p75NTR activity. Using the uncleavable pro-BDNF, an earlier study revealed that activation of p75NTR can enhance long-term depression (LTD) in hippocampus, an effect not observed in 3-4-week-old p75NTR null mice (Woo et al., 2005). Although it lacks a kinase domain, p75NTR can form multimeric complexes with many different protein partners such as TRAF2 and TRAF6 to activate downstream intracellular signaling cascades and ultimately influence cellular functions including apoptosis, neurite outgrowth and myelination (Gentry et al., 2004; Nykjaer et al., 2005). Hence, the levels of p75NTR-associated TRAF2 and TRAF6 in response to 200 ng/ml of BDNF can be used to gauge the effect of prenatal cocaine exposure on the efficiency of the p75NTR signaling. Figure 1 show BDNF (200 ng/ml)-induced TRAF2 and TRAF6 association with p75NTR is diminished in prenatal cocaine-exposed brains assessed at postnatal day 21. This data supports the notion that prenatal cocaine exposure dampens p75NTR function. Thus, in contrast with the TrkB that is upregulated along with a markedly reduced depolarization- and NMDA/glycine-induced BDNF/pro-BDNF release, p75NTR signaling is attenuated following in utero cocaine exposure during first 3weeks of postnatal life.
Moreover, we show cocaine exposure during gestation has opposite effects on TrkB and p75NTR signaling. The reduced p75NTR signaling favors a more effective BDNF-TrkB signaling even when BDNF release is reduced and thereby facilitates recovery from cocaine-induced synaptic damage incurred in utero. However, this compensation is not able to prevent prenatal cocaine-induced brain changes. These cocaine-elicited alterations in brain function likely predispose these individuals to neuropsychiatric disorders such as depression, anxiety and drug addiction, all of which are regulated by glutamatergic and BDNF-TrkB activity.
In conclusion, studies like ours that identify the molecular underpinnings of the brain’s vulnerabilities to prenatal cocaine exposure can aid therapeutic strategies to reduce brain dysfunction of children of pregnant cocaine abusers.
Figure 1. Reduced p75NTR signaling in both hippocampus and prefrontal cortex of P21 rats that have had exposed to cocaine in utero. *p < 0.01 compared to saline exposed controls. N = 4.
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