Decoding the mechanisms of neuronal wiring: a lesson from Trisomy 21

In the brain, astrocytes are key cells responsible for synapse formation and maintenance, providing trophic support to neurons, and for maintaining local homeostasis. Astrocytes, unlike neurons, show considerable variation through evolution. At a morphological level, human astrocytes are larger and anatomically more complex than invertebrate and rodent astrocytes. At a molecular level, human astrocytes show increased expression of known synaptogenic molecules, such as thrombospondins 2 and 4, which may reflect the increased complexity of human brain circuitry and function (Caceres, 2017). However, the precise molecular mechanisms behind synapse formation across species remain unclear. Protocadherins are a family of proteins that have been identified to regulate cell-cell interactions during neural development, in the generation of neuronal identities and synaptic specificity. In mouse and frogs, astrocytes appear to only express gamma protocadherins. It is intriguing that gene expression profiles in Trisomy 21 (Down Syndrome – DS) reveal expression changes only in this subcluster (Hajj 2016). By evaluating expression profiles of the protocadherin subclusters (alpha, beta, and gamma) across species (fruit fly, frog, mouse, primate, human), this project aims to establish a unique role for astrocytes in the formation of synapses. In particular, our aim is to establish what role, if any, protocadherins play in establishing the unique functional capabilities of the human CNS – as well as being linked to human intellectual disability