TrkB Receptor Ligands Promote Activity-Dependent Inhibitory Synaptogenesis

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.

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…BDNF promotion of inhibitory axon outgrowth and synapse formation is well characterized in hippocampus, cortex and, in particular, cerebellum in vitro and in vivo (Huang et al, 1999;Marty et al, 2000;Seil and Drake-Baumann, 2000;Yamada et al, 2002). Accordingly, fewer GABAergic synapses are observed in cerebellar slices following scavenging of endogenous BDNF (Seil and DrakeBaumann, 2000) and in conditional TrkB deletion mutants (Rico et al, 2002).…”

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

“…Recent studies have suggested a role for neurotrophins in the growth and refinement of neural connections, 43 dendritic arborization, 17 programmed cell death, 44 cortical lamination, 18,45 synaptogenesis, 46 and in activity-dependent synaptic plasticity. 47,48 Altered expression of NT3, NT4, trkB, and trkC as well as netrin 1 may have numerous potentially deleterious effects on cortical lamination during development. For example, an intriguing study demonstrated that administration of exogenous NT4 to organotypic cortical slice cultures results in dyslamination and neuronal heterotopia within cortical layers I to II.…”

“…50 Cell culture experiments revealed reduced survival by trkBϪ/Ϫ cortical neurons, a quantitatively significant defect in the formation of dendrites, and a significant reduction in neurite outgrowth by surviving trkBϪ/Ϫ neurons. 48 Reduced levels of netrin1 are associated with impaired axon pathfinding and aberrant neuronal migration. 51 …”

“…For example, BDNF and NT3 promote the morphological differentiation of a subpopulation of GABAergic neurons in cortex 53 and a recent study showed markedly diminished numbers of GABAergic neurons in tubers as evidenced by GAD65 immunolabeling. 37 Similarly, NT3 and trkB have a role in the promotion of activity-dependent inhibitory synaptogenesis 48,49 and thus, reduced NT3 and trkB expression may alter the formation of inhibitory synapses in tubers. Reduced expression of several GABA A receptor subunits has been demonstrated in tubers and thus, a reduction in GABAergic neurons coupled with diminished GABA-mediated receptor inhibition may foster epileptogenesis.…”

Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor

“…Previous evidence has shown that BDNF modulates the level of functional inhibition in an activity-dependent manner by regulating the number of GABAergic interneurons (Rutherford et al, 1997). Neuronal activity also modulates inhibitory synaptogenesis (Seil and Drake-Baumann, 1994;Marty et al, 2000), and this synapse formation is regulated by BDNF (Seil and Drake-Baumann, 2000). However, the long-term effects of BDNF on the strength of inhibitory synapses are unclear.…”