Fig. 3 ∣. Birth, migration and fate of cortical interneurons.

Cartoon of the typical trajectory of cortical IN development highlighting five critical stages of maturation that could proceed differently in autism. Many of the phenotypes observed in autism, whether reduced density of MGE-derived INs, mis-targeting of axons by PV neurons, network hypersynchrony or PV hypoactivity, could be traced back to an important checkpoint of postnatal development, when Pyr neurons and INs are first establishing functional connections (the 'handshake’). Whether one of these changes triggers the others and is the ultimate culprit of circuit dysfunction is not yet clear. a, Neurogenesis: birth of IN precursors at the MGE or caudal ganglionic eminence (CGE). Future PV and SST INs are generated in the CGE and express markers such as NKX2.1 and LHX6. b, Migration: MGE-derived and CGE-derived IN precursors migrate first tangentially and then radially into the cerebral cortex. Although cortical dysplasias described in some humans with autism could be explained by slower neuronal migration, changes in the migration of INs specifically have not been documented in autism. c, Apoptosis: a wave of developmental cell death in the second postnatal week is responsible for the loss of around 30% of cortical INs. Sensory-evoked and spontaneously generated cortical activity is responsible for this refinement in IN population density. Decreases in the intrinsic activity of INs (for example, due to immaturity) could lead to excessive death of INs in autism and explain the reduced density of PV neurons. d, Neurite extension: INs extend dendrites and axons in search of appropriate synaptic partners. IN hypoactivity could interfere with their ability to interact with Pyr neurons during an early acquaintance handshake or embrace between them. Immaturity of PV dendritic arbors has been reported in some mouse models of autism. e, Synaptic specialization: cortical INs eventually adopt their mature morphology and establish specialized synapses that target specific compartments of Pyr cells and other INs. This cell-type-specific structural connectivity is regulated by synaptic organizer proteins. It will be important to investigate whether differences exist in the expression of these genes, or in synaptic specificity, between autism models and controls.