Control of synapse development and plasticity by Rho GTPase regulatory proteins

Synapses are specialized cell–cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development.     

Neural plasticity after peripheral nerve injury and regeneration

Injuries to the peripheral nerves result in partial or total loss of motor, sensory and autonomic functions conveyed by the lesioned nerves to the denervated segments of the body, due to the interruption of axons continuity, degeneration of nerve fibers distal to the lesion and eventual death of axotomized neurons. Injuries to the peripheral nervous system may thus result in considerable disability. After axotomy, neuronal phenotype switches from a transmitter to a regenerative state, inducing the down- and up-regulation of numerous cellular components as well as the synthesis de novo of some molecules normally not expressed in adult neurons. These changes in gene expression activate and regulate the pathways responsible for neuronal survival and axonal regeneration. Functional deficits caused by nerve injuries can be compensated by three neural mechanisms: the reinnervation of denervated targets by regeneration of injured axons, the reinnervation by collateral branching of undamaged axons, and the remodeling of nervous system circuitry related to the lost functions. Plasticity of central connections may compensate functionally for the lack of specificity in target reinnervation; plasticity in human has, however, limited effects on disturbed sensory localization or fine motor control after injuries, and may even result in maladaptive changes, such as neuropathic pain, hyperreflexia and dystonia. Recent research has uncovered that peripheral nerve injuries induce a concurrent cascade of events, at the systemic, cellular and molecular levels, initiated by the nerve injury and progressing throughout plastic changes at the spinal cord, brainstem relay nuclei, thalamus and brain cortex. Mechanisms for these changes are ubiquitous in central substrates and include neurochemical changes, functional alterations of excitatory and inhibitory connections, atrophy and degeneration of normal substrates, sprouting of new connections, and reorganization of somatosensory and motor maps. An important direction for ongoing research is the development of therapeutic strategies that enhance axonal regeneration, promote selective target reinnervation, but are also able to modulate central nervous system reorganization, amplifying those positive adaptive changes that help to improve functional recovery but also diminishing undesirable consequences.     

Regulation of intrinsic neuronal properties for axon growth and regeneration

Regulation of neuritic growth is crucial for neural development, adaptation and repair. The intrinsic growth potential of nerve cells is determined by the activity of specific molecular sets, which sense environmental signals and sustain structural extension of neurites. The expression and function of these molecules are dynamically regulated by multiple mechanisms, which adjust the actual growth properties of each neuron population at different ontogenetic stages or in specific conditions. The neuronal potential for axon elongation and regeneration are restricted at the end of development by the concurrent action of several factors associated with the final maturation of neurons and of the surrounding tissue. In the adult, neuronal growth properties can be significantly modulated by injury, but they are also continuously tuned in everyday life to sustain physiological plasticity. Strict regulation of structural remodelling and neuritic elongation is thought to be required to maintain specific patterns of connectivity in the highly complex mammalian CNS. Accordingly, procedures that neutralize such mechanisms effectively boost axon growth in both intact and injured nervous system. Even in these conditions, however, aberrant connections are only formed in the presence of unusual external stimuli or experience. Therefore, growth regulatory mechanisms play an essentially permissive role by setting the responsiveness of neural circuits to environmental stimuli. The latter exert an instructive action and determine the actual shape of newly formed connections. In the light of this notion, efficient therapeutic interventions in the injured CNS should combine targeted manipulations of growth control mechanisms with task-specific training and rehabilitation paradigms.     

IL-10 production by B cells is differentially regulated by immune-mediated and infectious stimuli and requires p38 activation

IL-10 is an immune suppressive cytokine with pleiotropic effects on B cell biology. IL-10 production has a pivotal role for the regulatory suppressive functions that B cells exert in many physiological and pathological settings. Several exogenous stimuli and endogenous immune mediators can trigger IL-10-producing B cell maturation. To clarify and gain a better insight into the mechanisms of IL-10 production by B cells, we first compared the effects of LPS, CpG, agonistic CD40 mAb and BAFF on IL-10 production, and then we investigated the signal transduction mechanisms responsible for these responses. While infectious/danger stimuli determine the rapid production and release of IL-10 by B cells, a limited subset of CD40-poised, IL-10-competent B cells produce IL-10 in response to a later antigenic or infectious signal. Although BAFF is able to induce a similar subset of IL-10-competent B cells, these cells do not similarly respond to the same antigenic or infectious signals. Importantly, by using specific inhibitors of the MAP kinase pathways, we found that while il-10 gene expression triggered by the TLR agonists LPS and CpG is strongly dependent on p38 activity, the induction of IL-10 competence in CD40-activated B cells does not depend on ERK1/2, p38 or JNK pathways.