Cadherin‐8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits

Abstract

Neocortical interactions with dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson’s disease, and Huntington’s disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of molecular mechanisms that control generation of prefrontal cortex-striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin 8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in medial prefrontal cortex and in striatal medium spiny neurons forming the direct- or indirect-pathways. Developmental analysis of quantitative RTPCR and Western blot data show that Cdh8 expression peaks in prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron-microscopy shows Cdh8 is concentrated at excitatory synapses in dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses.

Localization of nectin‐2α at the boundary between the adjacent somata of the clustered cholinergic neurons and its regulatory role in the subcellular localization of the voltage‐gated A‐type K+ channel Kv4.2 in the medial habenula

“…The anti‐cadherin‐8 mAb (CAD8‐1, RRID:AB_2078272) developed by Dr. Masatoshi Takeichi (RIKEN CDB) was obtained from the Developmental Studies Hybridoma Bank (Iowa City, IA). The mAb recognized a 135‐kDa band in Western blotting of mouse prefrontal cortex and striatum (Friedman et al, ). Specificity was verified by Western blotting of the wild‐type and cdh8 ‐deficient mouse spinal cords (Suzuki et al, ).…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…Together with N -cadherin, CDH8 regulates the development of the hippocampal mossy fiber pathway (Bekirov et al, 2008). CDH8 also mediates assembly and maturation of corticostriatal synapses (Bekirov et al, 2008; Friedman et al, 2015b), whereas CDH9-mediated adhesion is involved in the formation and differentiation of dentate gyrus synapses on CA3 cells where it regulates synapse density, presynaptic bouton complexity and postsynaptic morphology (Williams et al, 2011). In contrast to CDH8 and CDH9, an RNAi screen for molecules required for synapse development identified CDH11 and CDH13 as positive regulators of glutamatergic synapse development (Paradis et al, 2007).…”

Probing disrupted neurodevelopment in autism using human stem cell‐derived neurons and organoids: An outlook into future diagnostics and drug development

“…CDH9/10 encode for cadherin-9 and cadherin-10, respectively, and are members of the cadherin family known to be involved in regulating many important neurodevelopmental processes, including neurogenesis, migration, neurite outgrowth, and synaptic specificity and plasticity. [248][249][250][251][252][253][254] CNTNAP2 encodes for Caspr2, another member of the neurexin family of proteins that is expressed in neurons and oligodendrocytes. 255 In neurons, Caspr2 acts as a scaffold and is necessary for K+ channel localization at the juxtaparanodal regions of myelinated axons.…”