Figure 12

PI3 Kinase and IP3 are Both Necessary and Sufficient to Mediate NT3-Induced Synaptic Potentiation
Yang, He, Feng, Liu
Neurotrophic factors have recently been recognized as an important class of neuromodulators for synapse development and plasticity. Two modes of actions have been observed: acute modulation of neuronal and synaptic activity and long-term regulation of the structures and function of synapses. The Unit on Synapse Development and Plasticity has demonstrated that the acute effect of neurtrophin-3 (NT3) on synaptic transmission at the neuromuscular junction (NMJ) can be blocked by inhibition of PI3 kinase and IP3 receptors. However, neither stimulation of Ca2+ release from intracellular stores by photolysis of caged IP3 nor expression of a constitutively active phosphoinositide-3 kinase (PI3K*) in presynaptic motoneurons alone is sufficient to enhance transmission. Remarkably, photo-uncaging of IP3 in neurons expressing PI3K* elicits a marked synaptic potentiation, mimicking the NT3 effect. Our research reveals a novel role of PI3 kinase in synaptic transmission and suggests a general principle that combinational use of signaling pathways determines the specificity of neurotrophin actions.

GDNF Acutely Modulates Neuronal Excitability and A-Type Potassium Channels in Midbrain Dopaminergic Neurons
Yang, Feng, Du
The unit has also studied the acute effect of glial-derived neurotrophic factor (GDNF) in the central nervous system (CNS). GDNF has long been thought to be a potent neurotrophic factor for the survival of midbrain dopaminergic neurons, which degenerate in Parkinson’s disease. However, all previous experiments were performed on injured neurons. The physiological function of GDNF on normal neurons is not known. The unit discovered an unexpected, acute effect of GDNF on A-type potassium channels that leads to a potentiation of neuronal excitability in dopaminergic neurons in culture as well as in adult brain slices. Further, it was found that GDNF regulates K+ channels through a mechanism that involves activation of MAP kinase. Thus, our study has revealed, for the first time, an acute modulation of ion channels by GDNF. These findings challenge the traditional view of GDNF as a long-term survival factor for midbrain dopaminergic neurons and suggest that the normal function of GDNF is to regulate neuronal excitability and, consequently, dopamine release. These results may have important implications in the treatment of Parkinson’s disease.

Protein Synthesis-Dependent and -Independent Regulation of Hippocampal Synapses by BDNF
Tartaglia, Du
While significant progress has been made in understanding the acute effects of neurotrophins at synapses, much less is known about the molecular mechanisms for the long-term synaptic effects. The unit has demonstrated that long-term treatment of hippocampal slices with BDNF induces a robust increase in the synaptic protein synaptotagmin. The effect can be blocked by inhibition of cAMP pathway and protein synthesis. These results suggest that, unlike acute modulation, long-term regulation of hippocampal synapses by BDNF requires protein synthesis and cAMP-molecular mechanisms very similar to those used in activity-dependent long-term synaptic modulation.

Ca2+-Binding Protein Frequenin Mediates GDNF-Induced Synaptic Facilitation by Potentiating Ca2+ Channels
Wang, Yang, He, Chow, Du
Using Xenopus nerve-muscle cocultures, the unit has also investigated the molecular mechanisms underlying the long-term effects of GDNF on synaptic transmission at the neuromuscular junction (NMJ). Long-term treatment with GDNF potentiates synaptic transmission at the NMJ in a manner very similar to that elicited by presynaptic expression of frequenin, a neuron-specific Ca2+-binding protein. GDNF enhances the expression of frequenin in motoneurons. Inhibition of frequenin expression or activity prevents the synaptic action of GDNF. GDNF also facilitates Ca2+ influx at the nerve terminals during evoked synaptic transmission by enhancing Ca2+ currents. The effect of GDNF on Ca2+ currents is blocked by inhibition of frequenin expression, occluded by overexpression of frequenin, and is selective to N-type Ca2+ channels. Thus, frequenin mediates GDNF-induced synaptic facilitation by potentiating N-type Ca2+ channels. These results have identified, for the first time, a molecular target that mediates the long-term synaptic action of a neurotrophic factor. Our findings may also have general implications in the cell biology of neurotransmitter release.