In development of the vertebrate hindbrain, segmentation of the neuroepithelium into rhombomeres is an early developmental step which provides a framework for correct neural connectivity [108] and rhombomere boundaries are associated with CSPG expression [109]. Within the cranial mesenchyme the correct rhombomeric projection of sensory trigeminal and facial/acoustic ganglia axons is thought to depend on such CSPG boundaries [110]. Additionally, commissural projections of vestibular nuclei neurones are regulated by CSPGs, where CS moieties have been shown to control guidance of pioneer axons, fasciculation and timing of axon arrival at the contralateral target [111]. In the visual

system CS-GAGs are implicated in extrinsic regulation of the divergence of retinal axons at the optic chiasm

selleck screening library midline (a developmental step which imparts binocular vision) [112] as well as repelling axons to confer retinal cell topography [113–115]. CSPGs in the developing CNS also act to modulate the properties of other guidance cues. The transmembrane protein semaphorin 5A (Sema5A) exerts proteoglycan-dependent signalling. Chondroitin sulphate/heparin sulphate-GAGs bind to thrombospondin repeats within Sema5a, switching it from an attractive to a repellent molecule to guide formation of the fasciculus retroflexus, a diencephalon fibre tract associated with limbic Selumetinib molecular weight function [116]. During postnatal development, the composition of the ECM gradually matures as neuronal circuitry approaches its adult form. Stabilization of connectivity is prefixed by a ‘critical period’ in which circuits are sensitive to experience-dependent plasticity. Ocular dominance plasticity is a classic system in which this has received much attention. Monocular deprivation during the critical period, but not in the

adult, causes cortical neurones to shift in coding preference to the nondeprived eye [117,118]. Studying the mechanisms by which the critical period is initiated and terminated is informative to approaches aiming to reactivate plasticity to promote repair following injury. The rate at which fast-spiking parvalbumin positive cortical interneurones mature (a process delayed by dark-rearing from birth) and release Enzalutamide supplier the neurotransmitter GABA is known to contribute to the onset of the critical period. The ECM also undergoes significant changes as the critical period closes. PNN formation coincides with critical period termination and attenuating PNN structure results in persistent ocular dominance plasticity in Ctrl1−/− mice [38]. Accordingly, as the critical period closes there is an upregulation of Ctrl1, aggrecan and HA [119]. CSPG expression is also associated with closure of the critical period [120]. Indeed dark rearing from birth, which extends the critical period, is associated with delayed expression of PNN CSPGs [121].