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International audience; One of the most intriguing features of inhibitory synapses is the precision by which they innervate their target, not only at the cellular level but also at the subcellular level (i.e. axo-dendritic, axo-somatic, or axo-axonic innervation). In particular, in the cerebellum, cortex, and spinal cord, distinct and highly specialized GABAergic interneurons, such as basket cells, chandelier cells, and GABApre interneurons, form precise axo-axonic synapses, allowing them to directly regulate neuronal output and circuit function. In this article, we summarize our latest knowledge of the cellular and molecular mechanisms that regulate the establishment and maintenance of axo-axonic synapses in these regions of the CNS. We also detail the key roles of the L1CAM family of cell adhesion molecules in such GABAergic subcellular target recognition.

Chandelier cells (ChCs) are a unique type of GABAergic interneuron that selectively innervate the axon initial segment (AIS) of excitatory pyramidal neurons; the subcellular domain where action potentials are initiated. The proper genesis and maturation of ChCs is critical for regulating neural ensemble firing in the neocortex throughout development and adulthood. Recently, genetic and molecular studies have shed new light on the complex innerworkings of ChCs in health and disease. This review presents an overview of recent studies on the developmental origins, migratory properties, and morphology of ChCs. In addition, attention is given to newly identified molecules regulating ChC morphogenesis and connectivity as well as recent work linking ChC dysfunction to neural disorders, including schizophrenia, epilepsy, and autism spectrum disorder (ASD).

Ample evidence indicates that individuals with intellectual disability (ID) are at increased risk of developing stress-related behavioral problems and mood disorders. Yet, a mechanistic explanation for such a link remains largely elusive. Here, we focused on characterizing the syndromic ID gene oligophrenin-1 (OPHN1). We find that Ophn1 deficiency in mice markedly enhances helpless/depressive-like behavior in the face of repeated/uncontrollable stress. Strikingly, Ophn1 deletion exclusively in parvalbumin (PV) interneurons in the prelimbic medial prefrontal cortex (PL-mPFC) is sufficient to induce helplessness. This behavioral phenotype is mediated by a diminished excitatory drive onto Ophn1-deficient PL-mPFC PV interneurons, leading to hyperactivity in this region. Importantly, suppressing neuronal activity or RhoA/Rho-kinase signaling in the PL-mPFC reverses helpless behavior. Our results identify OPHN1 as a critical regulator of adaptive behavioral responses to stress and shed light onto the mechanistic link between OPHN1 genetic deficits, mPFC circuit dysfunction, and abnormalities in stress-related behaviors.

Summary Among the diverse interneuron subtypes in the neocortex, chandelier cells (ChCs) are the only population that selectively innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, allowing them to exert powerful control over PyN output. Yet, mechanisms underlying their subcellular innervation of PyN AISs are unknown. To identify molecular determinants of ChC/PyN AIS innervation, we performed an in vivo RNAi screen of PyN-expressed axonal cell adhesion molecules (CAMs) and select Ephs/ephrins. Strikingly, we found the L1 family member L1CAM to be the only molecule required for ChC/PyN AIS innervation. Further, we show that L1CAM is required during both the establishment and maintenance of innervation, and that selective innervation of PyN AISs by ChCs requires AIS anchoring of L1CAM by the cytoskeletal ankyrin-G/βIV-spectrin complex. Thus, our findings identify PyN-expressed L1CAM as a critical CAM required for innervation of neocortical PyN AISs by ChCs. Video Abstract Download : Download video (46MB)