Brain-Derived Neurotrophic Factor and trkB Signaling in Parasympathetic Neurons: Relevance to Regulating α7-Containing Nicotinic Receptors and Synaptic Function

Abstract

Parasympathetic neurons do not require neurotrophins for survival and are thought to lack high-affinity neurotrophin receptors (i.e., trks). We report here, however, that mRNAs encoding both brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (trkB) are expressed in the parasympathetic chick ciliary ganglion (CG) and that BDNF-like protein is present in the ganglion and in the iris, an important peripheral target of ciliary neurons. Moreover, CG neurons express surface trkB and exogenous BDNF not only initiates trk-dependent signaling, but also alters nicotinic acetylcholine receptor (nAChR) expression and synaptic transmission. In particular, BDNF applied to CG neurons rapidly activates cAMP-dependent response element-binding protein (CREB), and over the long-term selectively upregulates expression of ␣7-subunit-containing, homomeric nAChRs (␣7-nAChRs), increasing ␣7-subunit mRNA levels, ␣7-nAChR surface sites, and ␣7-nAChR-mediated whole-cell currents. At nicotinic synapses formed on CG neurons in culture, brief and long-term BDNF treatments also increase the frequency of spontaneous EPSCs, most of which are mediated by heteromeric nAChRs containing ␣3, ␣5, ␤4, and ␤2 subunits (␣3*-nAChRs) with a minor contribution from ␣7-nAChRs. Our findings demonstrate unexpected roles for BDNF-induced, trk-dependent signaling in CG neurons, both in regulating expression of ␣7-nAChRs and in enhancing transmission at ␣3*-nAChR-mediated synapses. The presence of BDNF-like protein in CG and iris target coupled with that of functional trkB on CG neurons raise the possibility that signals generated by endogenous BDNF similarly influence ␣7-nAChRs and nicotinic synapses in vivo.

Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

“…The link between A 2A Rs and BDNF is well-documented, with evidence showing that A 2A R activation is necessary both for regulating the expression and release of BDNF in the brain, and mediating BDNF's effects on synaptic plasticity (reviewed in Sebastiao and Ribeiro, 2009). In neurons cultured from the hippocampus and the ciliary ganglion, BDNF is known to upregulate the intracellular and surface pools of α7, but not β2* nAChRs (Massey et al, 2006;Zhou et al, 2004). In addition, the interplay of A 2A Rs with BDNF and α7 nAChRs is evidenced in the fact that adenosine deaminase or A 2A R antagonists abolish the effects of BDNF on α7 nAChR function (Fernandes et al, 2008).…”

Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis

“…Expression of transcripts encoding Hand2 was determined by in situ hybridization or by qRT-PCR according to our previously published methods (Wu and Howard, 2002;Zhou et al, 2004;Ruest et al, 2004;Liu et al, 2005;Hendershot et al, 2007).…”

Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

“…Although the active component in cigarette smoke is not yet known, accumulating evidence points to a role for nicotine as a contributor to this apparent neuroprotective effect (O'Neill et al, 2002;Quik, 2004). Support for this possibility stems from studies showing that exposure of cultured cells to nicotine attenuates cellular degeneration (Jin et al, 2004;Papke et al, 2004;Zhou et al, 2004), including damage induced by neurotoxins that selectively destroy dopamine neurons (Jeyarasasingam et al, 2002). In vivo studies also indicate that nicotine protects against nigrostriatal damage, although inconsistencies have been observed in rodent models that may relate to the specific experimental paradigms used, species, or other factors (Janson et al, 1992;Hadjiconstantinou et al, 1994;Costa et al, 2001;Ryan et al, 2001;O'Neill et al, 2002;Parain et al, 2003;Quik, 2004).…”