The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

Abstract

The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain-and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1-induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.

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“…Neurotrophic factors such as BDNF and GDNF play a role in the development and maintenance of dendritic spines . This suggests that alterations in expression of neurotrophic factors may underlie changes in spine proportion.…”

“…In general, dendritic spines with large heads and mature shapes, such as mushroom and branched spines, contribute strongly to synaptic stability and connection, while spines with small heads and immature shapes, such as thin and stubby spines, form weak synaptic connections . GDNF can promote development of dendritic spines . This led us to speculate that increased GDNF expression plays an important role in the development of dendritic spines and enhancement of synaptic connections in PRE‐treated mice.…”

“…PRE may selectively reverse the epigenetic modification of the promoter region. Stronger GDNF family receptor (GFR)α1 expression seems to be observed in the DG than in the CA1 or CA3 . The distribution of GFRα1, a GDNF receptor, could be involved in the difference in reaction to PRE between the CA1 and DG.…”

“…Maintenance and regulation of hippocampal neurogenesis and spine density are affected by several neurotrophic factors such as brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived neurotrophic factor (GDNF) . In clinical studies these neurotrophic factors were decreased in serum and leukocytes of depressed patients, and were normalized by treatment with antidepressants .…”

Diolistic Labeling and Analysis of Dendritic Spines

“…Additionally, individual spines are activated by TrkB, which controls structural and functional plasticity ( 4 ) . Glial cell line-derived neurotrophic factor and its receptor GFRαl play an important role in dendritic growth and spine formation in the hippocampus ( 3,5 ) . In several neurodevelopmental disorders, growth factors are mutated and lead to intellectual disability and stereotypies such as those that occur in Rett syndrome ( 6 ) .…”