Neurotrophic factor regulation of developing avian oculomotor neurons: Differential effects of BDNF and GDNF

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.

Section: Functional Relevance Of Bdnf and Trkbmentioning

confidence: 65%

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

Zhou¹,

Nai²,

Chen³

et al. 2004

“…Stimulation with multiple, but not individual, NTFs completely rescues adductor motor neurons from PCD Although NTF treatment has previously been observed to be incapable of rescuing some populations of NTF-R-positive MNs from death (Steljes et al, 1999;Caton et al, 2000;Novak et al, 2000), this effect extended to an entire subpopulation of competing MNs. In contrast, we showed that such subpopulations themselves are heterogeneous in responding to specific NTFs.…”

Section: Ntf-rs Are Expressed Heterogeneously In the Spinal Cord And mentioning

confidence: 96%

“…Similarly, although the receptors for HGF and BDNF are expressed by the oculomotor nucleus, neither excess HGF nor BDNF rescue these MNs from PCD (Steljes et al, 1999;Caton et al, 2000;Novak et al, 2000). However, inhibition of other specific NTF signaling pathways does result in the increased death of some subsets of spinal MNs during the period of PCD (Garcés et al, 2000;Novak et al, 2000;Oppenheim et al, 2000Oppenheim et al, , 2001Forger et al, 2003).…”

Section: Gdnf and Cntf Signaling Are Not Necessary For Adductor Mn Sumentioning

confidence: 99%

The Function of Neurotrophic Factor Receptors Expressed by the Developing Adductor Motor PoolIn Vivo

Gould¹,

Oppenheim²

2004

We examined the spatio-temporal relationship between neurotrophic factor receptor (NTF-R) expression and motoneuron (MN) survival in the developing avian spinal cord and observed heterogeneity in the expression of NTF-Rs between, but not within, pools of MNs projecting to individual muscles. We then focused on the role of NTFs in regulating the survival of one motor pool of MNs, all of which innervate a pair of adductor muscles in the thigh and hence compete for survival during the period of programmed cell death (PCD). The complete NTF-R complement of these MNs was analyzed and found to include many, but not all, NTF-Rs. Treatment with exogenous individual NTFs rescued some, but not all, adductor MNs expressing appropriate NTF-Rs. In contrast, administration of multiple NTFs completely rescued adductor MNs from PCD. Additionally, adductor MNs were partially rescued from PCD by NTFs for which they failed to express receptors. NTF-Rs expressed by the nerve but not in the muscle target were capable of mediating survival signals to MNs in trans. Finally, the expression of some NTF-Rs by adductor MNs was not required for MN survival. These studies demonstrate the complexity in NTF regulation of a defined subset of competing MNs and suggest that properties other than NTF-R expression itself can play a role in mediating trophic responses to NTFs.

“…Retrograde signals derived from muscle are believed to mediate or influence motoneuron survival during development (Steljes et al, 1999;Oppenheim et al, 2001). It seems unlikely that any retrograde signaling based on AChR activation in muscle is needed for adult motoneuron survival because adult motoneurons survive peripheral axotomy for extended periods when denied reinnervation (Vanden Noven et al, 1993).…”

Section: Roles Of Retrograde Signalingmentioning

confidence: 99%

Regulation of Motoneuron Excitability via Motor Endplate Acetylcholine Receptor Activation

Nakanishi¹,

Cope²,

Rich³

et al. 2005

Motoneuron populations possess a range of intrinsic excitability that plays an important role in establishing how motor units are recruited. The fact that this range collapses after axotomy and does not recover completely until after reinnervation occurs suggests that muscle innervation is needed to maintain or regulate adult motoneuron excitability, but the nature and identity of underlying mechanisms remain poorly understood. Here, we report the results of experiments in which we studied the effects on rat motoneuron excitability produced by manipulations of neuromuscular transmission and compared these with the effects of peripheral nerve axotomy. Inhibition of acetylcholine release from motor terminals for 5-6 d with botulinum toxin produced relatively minor changes in motoneuron excitability compared with the effect of axotomy. In contrast, the blockade of acetylcholine receptors with ␣-bungarotoxin over the same time interval produced changes in motoneuron excitability that were statistically equivalent to axotomy. Muscle fiber recordings showed that low levels of acetylcholine release persisted at motor terminals after botulinum toxin, but endplate currents were completely blocked for at least several hours after daily intramuscular injections of ␣-bungarotoxin. We conclude that the complete but transient blockade of endplate currents underlies the robust axotomy-like effects of ␣-bungarotoxin on motoneuron excitability, and the low level of acetylcholine release that remains after injections of botulinum toxin inhibits axotomy-like changes in motoneurons. The results suggest the existence of a retrograde signaling mechanism located at the motor endplate that enables expression of adult motoneuron excitability and depends on acetylcholine receptor activation for its normal operation.