Abstract
Neuronal transmission is regulated by the local circuitry which is composed of principal neurons targeted at different subcellular compartments by a variety of interneurons. However, mechanisms that contribute to the subcellular localisation and maintenance of GABAergic interneuron terminals are poorly understood. Stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin and its interaction with the guanine nucleotide exchange factor collybistin. Lentiviral knockdown experiments in adult rats indicated that the receptor tyrosine kinase EphA7 is required for the stabilisation of basket cell terminals on proximal dendritic and somatic compartments of granular cells of the dentate gyrus. EphA7 deficiency and concomitant destabilisation of GABAergic synapses correlated with impaired long-term potentiation and reduced hippocampal learning. Reduced GABAergic innervation may be explained by an impact of EphA7 on gephyrin clustering. Overexpression or ephrin stimulation of EphA7 induced gephyrin clustering dependent on the mechanistic target of rapamycin (mTOR) which is an interaction partner of gephyrin. Gephyrin interactions with mTOR become released after mTOR activation while enhanced interaction with the guanine nucleotide exchange factor collybistin was observed in parallel. In conclusion, EphA7 regulates gephyrin clustering and the maintenance of inhibitory synaptic connectivity via mTOR signalling.
Highlights
Considering candidate receptors involved in the subcellular control of gephyrin clustering, we regarded EphA7 as an interesting candidate expressed on dendritic and somatic compartments of granule cells in the hippocampus[12]
We have shown that the receptor tyrosine kinase EphA7 is required for the stabilisation of basket cell innervation on proximal dendrites and somata of dentate gyrus granule cells
In vitro experiments indicated that EphA7-dependent gephyrin clustering relies on the protein kinase activity of EphA7 and depends on the activation of mechanistic target of rapamycin (mTOR). mTOR activation coincides with reduced gephyrin-mTOR interaction and increases interaction of gephyrin with collybistin
Summary
Considering candidate receptors involved in the subcellular control of gephyrin clustering, we regarded EphA7 as an interesting candidate expressed on dendritic and somatic compartments of granule cells in the hippocampus[12]. EphA7 is a member of a subclass of eight receptor tyrosine kinases interacting with five different ephrin A ligands in a highly promiscuous way[13]. Ephrin ligands are membrane-bound, suggesting a role in cell-cell interaction and trans-synaptic signalling. We identify EphA7 as a cell surface receptor required for the stabilisation of synaptic terminals of parvalbumin-positive basket cells targeting somata and proximal dendrites of granule cells, the principal neurons of the rat dentate gyrus. We provide evidence that EphA7 induces gephyrin clustering via PI3K-Akt-mTOR signalling
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