The classic cadherins in synaptic specificity

Abstract

During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions.

Keywords: ADHD, attention deficit/hyperactivity disorder; BC, bipolar cell; DG, dentate gyrus; DN-cadherin, Drosophila N-cadherin; EC, extracellular cadherin; EGF, epidermal growth factor.; RGCs, retinal ganglion cells; SNPs, single nucleotide polymorphisms; classic cadherins; cognitive disorders; molecular identity; synaptic specificity.

Figure 1.

Structure of the classic cadherin protein family in humans. All classic cadherins have 5 extracellular cadherin (EC) repeats, a transmembrane (TM) domain, and an intracellular domain (ICD) that binds p120-catenin and β-catenin. The classic cadherins are sub-divided into Type I and Type II depending on the presence of a histidine-alanine-valine (HAV) motif in the first EC domain. Human Type I and Type II cadherins are indicated as annotated in the HUGO Gene Nomenclature Committee database with common names noted in parentheses.

Figure 2.

Model of Type II cadherin mediated synaptic specificity. (A) Illustration depicting a 3 neuron circuit with specific connections from neuron 1 to neuron 2 and then neuron 2 to neuron 3. (B) Expanded view of synaptic areas circled in A. Note that all 3 neurons express the Type-I N-cadherin (pink), which is present and required for function of most synapses. However, the neurons express different kinds of Type II cadherins (orange or purple) to restrict synapse formation to select synaptic partners that express the matching Type II cadherin.