Where no synapses go: gatekeepers of circuit remodeling and synaptic strength

Abstract

Growth inhibitory molecules in the adult mammalian CNS have been implicated in blocking axonal sprouting and regeneration following injury. Prominent CNS regeneration inhibitors include Nogo-A, OMgp and CSPGs, and a key question concerns their physiological role in the naïve CNS. Emerging evidence suggests novel functions in dendrites and at synapses of glutamatergic neurons. CNS regeneration inhibitors target the neuronal actin cytoskeleton to regulate dendritic spine maturation, long-term synapse stability, and Hebbian forms of synaptic plasticity. This is accomplished in part by antagonizing plasticity-promoting signaling pathways activated by neurotrophic factors. Altered function of CNS regeneration inhibitors is associated with mental illness and loss of long-lasting memory, suggesting unexpected and novel physiological roles for these molecules in brain health.

CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi apparatus

“…Growth-inhibitory mechanisms can play an important role in proper neuronal wiring, preventing excessive development of the neuronal network. Hyaluronan is one of the best-known growth-and regeneration-inhibiting molecules in the mammalian CNS (Mironova and Giger, 2013). Therefore, our findings that CD44, the main hyaluronan receptor, inhibits dendritogenesis provide new insights in this field.…”

AMPK agonist AICAR improves cognition and motor coordination in young and aged mice

“…Indeed, inactivation of the RCAN2 gene in mice also ameliorates age-and diet-induced obesity by causing a reduction in food intake (Sun et al 2011). Down-regulation was also found for ERRFI1 (reduces cell proliferation and muscle growth by inhibiting EGFR protein [Segatto et al 2011], Tang 2008, 2013], and dendritic spine stabilization [Mironova and Giger 2013], 2.07-fold), GOLGA2 (axonogenesis, 1.94-fold), and FGF13 (encodes for a protein member of the fibroblast growth factor [FGF] family, 2.03-fold). FGFs possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development cell growth (Wu et al 2012).…”

Cell biology of spinal cord injury and repair

“…Their effects on local synapse plasticity may be more relevant than effects on axon regrowth across lesions. For example, aggrecan, the prototypical CSPG used to demonstrate axon-inhibitory effects in vitro (95,101), is not detectably present in SCI lesion core or astrocyte scar, but it is heavily present in perineuronal nets in spared and reorganizing neural tissue, where it may restrict synaptic plasticity (19,(102)(103)(104). Although NG2 (encoded by Cspg4) can inhibit axon growth in vitro, multiple in vivo studies show that robust axon regrowth occurs in the presence of NG2 and that deletion of Cspg4 does not induce spontaneous axon regeneration (71)(72)(73)(74).…”

“…Deleting or blocking myelin is not sufficient to enable long-distance axon regrowth across severe SCI lesions and non-neural lesion cores (98,105,106). Thus, beneficial behavioral effects reported after blocking of either myelin-associated growth inhibitors or CSPG signaling are likely to be related to effects on synaptic plasticity and circuit reorganization after incomplete SCI ( Figure 3B) rather than to enabling of axon regrowth across anatomically complete SCI (99,102,104,107,108). It also should be emphasized that molecular cues are not absolute, such that exposure to specific growth factors can reprogram growth cones to ignore inhibitory cues both during development and after injury (42,43,82).…”

“…The perineuronal net, composed of matrix molecules including multiple CSPGs and tenascins, constrains synaptic plasticity and circuit reorganization (102,104). During postnatal development, the perineuronal net is involved in closing critical periods of synaptic plasticity, such that enzymatic digestion of the perineuronal net by chondroitinase can reopen that plasticity (104,127).…”