Glutamatergic axon-derived BDNF controls GABAergic synaptic differentiation in the cerebellum.

Eliezer Masliah,Louis F Reichardt,Albert I Chen,Keling Zang

doi:10.1038/srep20201

Abstract

To study mechanisms that regulate the construction of inhibitory circuits, we examined the role of brain-derived neurotrophic factor (BDNF) in the assembly of GABAergic inhibitory synapses in the mouse cerebellar cortex. We show that within the cerebellum, BDNF-expressing cells are restricted to the internal granular layer (IGL), but that the BDNF protein is present within mossy fibers which originate from cells located outside of the cerebellum. In contrast to deletion of TrkB, the cognate receptor for BDNF, deletion of Bdnf from cerebellar cell bodies alone did not perturb the localization of pre- or postsynaptic constituents at the GABAergic synapses formed by Golgi cell axons on granule cell dendrites within the IGL. Instead, we found that BDNF derived from excitatory mossy fiber endings controls their differentiation. Our findings thus indicate that cerebellar BDNF is derived primarily from excitatory neurons—precerebellar nuclei/spinal cord neurons that give rise to mossy fibers—and promotes GABAergic synapse formation as a result of release from axons. Thus, within the cerebellum the preferential localization of BDNF to axons enhances the specificity through which BDNF promotes GABAergic synaptic differentiation.

Highlights

Neurotrophic factor signaling is essential for the development of the nervous system and the absence of neurotrophins or their receptors have been linked to developmental and behavioral disorders including depression, bipolar disorder, addiction, anxiety, obesity and many neurodegenerative diseases[1]
Bdnf expression is restricted to the internal granular layer and the protein is localized on granule cell axons and mossy fiber endings
To explore the impact of mossy fibers on GABAergic synapse formation in the internal granular layer (IGL), we examined cerebellar slices cultured from P14-21 in vitro and compared these to P21 slices acutely prepared from 5 mice

Summary

Introduction

Neurotrophic factor signaling is essential for the development of the nervous system and the absence of neurotrophins or their receptors have been linked to developmental and behavioral disorders including depression, bipolar disorder, addiction, anxiety, obesity and many neurodegenerative diseases[1]. BDNF transcription, translation, processing, and secretion are controlled, in part, by synaptic activity[4,5,18,19,20,21]; the surface expression of TrkB and signaling after BDNF binding are controlled through membrane trafficking processes that are controlled, in part, via synaptic activity[22,23] Both BDNF release and cerebellar development are impaired in mice lacking CAPS2, a MUNC13 homologue that promotes activity-dependent BDNF release[13,14,24], suggesting that BDNF is an important effector in activity-stimulated cerebellar development and circuit maturation. Their targets to regulate the formation and maintenance of inhibitory synapses and localization of proteins and organelles associated with these synapses[9,12], the sources of BDNF involved in controlling GABAergic synapses within the cerebellar cortex were not determined in these studies. The subcellular localization of BDNF in cell-types that express BDNF and whether BDNF exerts its activities through axons and/or dendrites remain controversial[14,18,19,30,31]

Methods

Results

Conclusion