IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype

Abstract

The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

Neuromodulatory control of inhibitory network arborization in the developing postnatal neocortex

“…Consistent with our previous work ( 52 , 53 ), the transplanted MGE progenitors produced morphologically identifiable ChCs that reside at the border between L1 and uL2/3 and develop synaptic cartridges apposed to AISs following their intrinsic developmental program. Our recent study showed that these transplanted ChCs express ChC markers and establish normal synapses on AISs electrophysiologically/ultrastracturally indistinguishable from those of endogenous ChCs ( 53 ). To further validate the identity of transplanted ChCs, we examined other properties of endogenous ChCs.…”

To Stick or Not to Stick: The Multiple Roles of Cell Adhesion Molecules in Neural Circuit Assembly

“…Likewise in the cerebellum, Cdh7 mediates synapse formation between pontine axons and granule neurons ( Kuwako et al, 2014 ). More recently, IgSF11 has been identified as the homophilic adhesion molecule controlling synapse formation between inhibitory chandelier cells and pyramidal neurons in the cortex ( Hayano et al, 2021 ).…”

The IgCAM BT-IgSF (IgSF11) is essential for connexin43-mediated astrocyte-astrocyte and ependymal cell-cell coupling in mice

“…Consequently, global BT-IgSF-deficient mice displayed a moderately decreased excitatory synaptic strength in the dentate gyrus and long-term potentiation in hippocampal CA1 (Jang et al, 2015). In another study in neurons BT-IgSF was found to regulate the innervation of axons of chandelier cells on initial axon segments of pyramidal neurons (Hayano et al, 2021).…”

“…So far, the function of BT-IgSF (IgSF11) has been studied in neurons, Sertoli and germ cells of the testes, during osteoclast differentiation and in the organization of pigment cells in fish (Ahi and Sefc, 2017; Chen et al, 2021; Eom et al, 2012; Hayano et al, 2021; Jang et al, 2015; Kim et al, 2020; Pelz et al, 2017; Singh and Nusslein-Volhard, 2015). Knockdown studies using cultured mouse hippocampal neurons indicated that BT-IgSF is implicated in synaptic transmission through a tripartite interaction with PSD95 and AMPA receptors (Jang et al, 2015).…”