The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.

E Anne Martin,Jennifer Hunter,Scott A Wilke,Zhirong Wang,Tyler Cutforth,Raunak Basu,Anirvan Ghosh,Diégo Cordero Cervantes,Megan E Williams,Matthew R Taylor,Shruti Muralidhar

doi:10.7554/elife.09395

E Anne Martin, Jennifer Hunter + Show 9 more

Open Access

https://doi.org/10.7554/elife.09395

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Abstract

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.

Highlights

Executing cognitive tasks requires coordination among neural circuits
Given the association between Kirrel3 mutations and intellectual disabilities, we investigated the role of Kirrel3 in hippocampal circuits, which are critical for learning and memory, and may be impaired in patients with intellectual disabilities
We demonstrate Kirrel3 is required for normal development of mossy fiber (MF) filopodia, the synaptic structures connecting dentate granule (DG) and GABA neurons

Summary

Introduction

Executing cognitive tasks requires coordination among neural circuits. neurons usually send and receive neural information with different synaptic partners. One way neurons differentially regulate activity among partners is by forming different types of synapses with each partner (Williams et al, 2010; Emes and Grant, 2012) This kind of synaptic target specificity is exquisitely exemplified by hippocampal mossy fiber (MF) synapses. Main bouton and filopodial MF synapses are physically linked, they have different molecular and functional properties (Toth et al, 2000; McBain, 2008). This suggests DG neurons utilize specific cues to construct different types of synapses with CA3 and GABA neurons, but the identity of the target-specific cues is unknown

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