Abstract
SummaryFine orchestration of excitatory and inhibitory synaptic development is required for normal brain function, and alterations may cause neurodevelopmental disorders. Using sparse molecular manipulations in intact brain circuits, we show that the glutamate receptor delta-1 (GluD1), a member of ionotropic glutamate receptors (iGluRs), is a postsynaptic organizer of inhibitory synapses in cortical pyramidal neurons. GluD1 is selectively required for the formation of inhibitory synapses and regulates GABAergic synaptic transmission accordingly. At inhibitory synapses, GluD1 interacts with cerebellin-4, an extracellular scaffolding protein secreted by somatostatin-expressing interneurons, which bridges postsynaptic GluD1 and presynaptic neurexins. When binding to its agonist glycine or D-serine, GluD1 elicits non-ionotropic postsynaptic signaling involving the guanine nucleotide exchange factor ARHGEF12 and the regulatory subunit of protein phosphatase 1 PPP1R12A. Thus, GluD1 defines a trans-synaptic interaction regulating postsynaptic signaling pathways for the proper establishment of cortical inhibitory connectivity and challenges the dichotomy between iGluRs and inhibitory synaptic molecules.
Highlights
Synapses constitute the elementary functional units of the brain
By depleting glutamate receptor delta-1 (GluD1) in vivo in a few layer 2/3 cortical pyramidal neurons (CPNs) using sparse in utero electroporation (IUE), we demonstrate that GluD1 regulates the formation of inhibitory synapses in dendrites as well as inhibitory synaptic transmission
GluD1 Is Selectively Required for the Formation of Inhibitory Synapses In order to assess the role of GluD1 in synaptic development, we used cortex-directed IUE at embryonic day (E)15.5
Summary
Synapses constitute the elementary functional units of the brain. They convey excitatory or inhibitory signals that need to be coordinated in space and time for optimal brain function (Mullins et al, 2016; Nelson and Valakh, 2015). Excitatory and inhibitory synapses in the mammalian brain mainly use glutamate and gamma-aminobutyric acid (GABA) as a neurotransmitter, respectively They are multi-molecular nanomachines composed of almost exclusive sets of proteins (Krueger-Burg et al, 2017; Sheng and Kim, 2011; Tyagarajan and Fritschy, 2014). Trans-synaptic molecular interactions critically contribute to both the development and diversification of synaptic connections They instruct the formation of synapses following initial contact (McAllister, 2007; Missler et al, 2012), match pre- and post-synaptic neurons (Berns et al, 2018; de Wit and Ghosh, 2016), control the recruitment of neurotransmitter receptors and postsynaptic scaffolding proteins (Aoto et al, 2013; Bemben et al, 2015; Fukata et al, 2006; Lovero et al, 2015; Mondin et al, 2011; Nam and Chen, 2005; Poulopoulos et al, 2009), and regulate synaptic plasticity (Bemben et al, 2015; Jang et al, 2017; Tai et al, 2008; Yuzaki and Aricescu, 2017). The scarcity of information on how trans-synaptic signals are transduced in the post-synaptic neuron stymies our understanding of the molecular logic governing the assembly of synaptic connections
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