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TrkB receptor ligands promote activity-dependent inhibitory synaptogenesis
1Neurology Research, Veterans Affairs Medical Center and Departments of Neurology and Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201, USA. seilf@ohsu.edu
Abstract:
Organotypic cerebellar cultures derived from newborn mice were simultaneously exposed to activity-blocking agents and neurotrophins for 2 weeks. Activity-blocked explants treated with the TrkB receptor ligands BDNF and neurotrophin-4 (NT-4) developed a full complement of Purkinje cell inhibitory axosomatic synapses, as defined ultrastructurally, and displayed control spontaneous cortical discharge rates after recovery from activity blockade. Otherwise untreated activity-blocked cultures and activity-blocked cultures exposed to the TrkC receptor ligand NT-3 had reduced inhibitory synapse development and persistent cortical hyperactivity after recovery. The added TrkB receptor ligands did not induce axonal sprouting to account for increased inhibitory synaptogenesis. Addition of neurotrophins to untreated cerebellar cultures did not increase the complement of Purkinje cell axosomatic synapses. Exposure of cerebellar cultures to a combination of antibodies to BDNF and NT-4 resulted in reduced inhibitory synapse formation, similar to the effects of activity blockade, indicating the necessity for endogenous neurotrophins for development of the full complement of inhibitory synapses in the presence of neuronal activity. Application of antibodies to BDNF and NT-4 to cerebellar explants exposed to picrotoxin to increase neuronal activity prevented the hyperinnervation of Purkinje cell somata by inhibitory terminals characteristic of cultures exposed to picrotoxin alone. These results are consistent with the concept that TrkB receptor ligands promote inhibitory synaptogenesis. The ability of neurotrophins to substitute for neuronal activity in encouraging development of inhibitory synapses may have therapeutic implications.
Insights
Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) promote inhibitory synapse development in Purkinje cells. These neurotrophins can substitute for neuronal activity, offering potential therapeutic benefits.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Neuronal activity is crucial for proper synapse development.
- Neurotrophins are key signaling molecules regulating neuronal survival and function.
- Purkinje cells in the cerebellum form critical inhibitory synapses.
Purpose of the Study:
- To investigate the role of neurotrophins, specifically BDNF and NT-4, in the development of inhibitory synapses on Purkinje cells.
- To determine if neurotrophins can compensate for the absence of neuronal activity in synapse formation.
- To explore the therapeutic potential of neurotrophins in conditions affecting synaptic development.
Main Methods:
- Organotypic cerebellar cultures from newborn mice were used.
- Cultures were exposed to activity-blocking agents and various neurotrophins (BDNF, NT-4, NT-3) or antibodies.
- Synapse development was assessed ultrastructurally, and neuronal activity was measured after recovery.
Main Results:
- TrkB receptor ligands (BDNF, NT-4) restored inhibitory synapse development and normalized activity in cultures blocked from neuronal activity.
- TrkC ligand NT-3 did not rescue synapse development, and activity-blocked cultures showed reduced synapses and hyperactivity.
- Endogenous BDNF and NT-4 are necessary for normal inhibitory synapse formation.
- Antibodies to BDNF and NT-4 prevented activity-dependent hyperinnervation.
Conclusions:
- TrkB receptor ligands, BDNF and NT-4, are potent promoters of inhibitory synaptogenesis.
- Neurotrophins can substitute for neuronal activity in driving the development of inhibitory synapses.
- These findings suggest a therapeutic strategy for neurological disorders characterized by impaired synaptic development.