Astrocytes are the most prevalent glial cells in the brain. Historically considered as “merely supporting” neurons, recent research has shown that astrocytes actively participate in a large variety of central nervous system (CNS) functions including synaptogenesis, neuronal transmission and synaptic plasticity. During disease and injury, astrocytes efficiently protect neurons by various means, notably by sealing them off from neurotoxic factors and repairing the blood-brain barrier. Their ramified morphology allows them to perform diverse tasks by interacting with synapses, blood vessels and other glial cells. In this review article, we provide an overview of how astrocytes acquire their complex morphology during development. We then move from the developing to the mature brain, and review current research on perisynaptic astrocytic processes, with a particular focus on how astrocytes engage synapses and modulate their formation and activity. Comprehensive changes have been reported in astrocyte cell shape in many CNS pathologies. Factors influencing these morphological changes are summarized in the context of brain pathologies, such as traumatic injury and degenerative conditions. We provide insight into the molecular, cellular and cytoskeletal machinery behind these shape changes which drive the dynamic remodeling in astrocyte morphology during injury and the development of pathologies.

Profilins are small proteins involved in actin dynamics. In accordance with this function, they are found in all eukaryotes and are structurally highly conserved. However, their precise role in regulating actin-related functions is just beginning to emerge. This article recapitulates the wealth of information on structure, expression and functions accumulated on profilins from many different organisms in the 30 years after their discovery as actin-binding proteins. Emphasis is given to their interaction with a plethora of many different ligands in the cytoplasm as well as in the nucleus, which is considered the basis for their various activities and the significance of the tissue-specific expression of profilin isoforms.

Two profilin isoforms (PFN1 and PFN2a) are expressed in the mammalian brain. Although profilins are essential for regulating actin dynamics in general, the specific role of these isoforms in neurons has remained elusive. We show that knockdown of the neuron-specific PFN2a results in a significant reduction in dendrite complexity and spine numbers of hippocampal neurons. Overexpression of PFN1 in PFN2a-deficient neurons prevents the loss of spines but does not restore dendritic complexity. Furthermore, we show that profilins are involved in differentially regulating actin dynamics downstream of the pan-neurotrophin receptor (p75 NTR ), a receptor engaged in modulating neuronal morphology. Overexpression of PFN2a restores the morphological changes in dendrites caused by p75 NTR overexpression, whereas PFN1 restores the normal spine density. Our data assign specific functions to the two PFN isoforms, possibly attributable to different affinities for potent effectors also involved in actin dynamics, and suggest that they are important for the signal-dependent finetuning of neuronal architecture.N euronal plasticity depends on functional changes at synapses and, additionally, on the spatial and temporal modulation of neuronal architecture, which is induced by the transmission of external signals to the cytoskeleton. Among the proteins engaged in the organization of the actin cytoskeleton are profilins (1) that bind to monomeric actin, polyproline-stretch proteins, and membranebound phospholipids (reviewed in ref.2). In the mammalian brain, two different profilin isoforms are found: profilin 1 (PFN1), which is ubiquitously expressed in all eukaryotic cells, and profilin 2a (PFN2a), which is tissue-restricted and shows its highest expression level in the brain (3, 4). The cell-and tissue-specific role of profilins remains poorly understood. In particular, the precise function of neuronal PFN2a is still unclear. Recent evidence points to pre-and postsynaptic functions of both isoforms. Experiments with cultured hippocampal neurons revealed activity-dependent targeting of PFN1 (5) and PFN2a (6) into spines of excitatory neurons. Furthermore, Lamprecht et al. (7) demonstrated a stimulus-dependent accumulation of profilin, without isoform specification, in spines of neurons in the rat amygdala. In addition, NMDA receptor activation was seen to correlate with changes in spine morphology, a process apparently involving PFN2a, RhoA, and the RhoA-specific kinase ROCK (8). In contrast, data derived from a KO mouse indicate that PFN2a acts presynaptically, by controlling vesicle exocytosis and presynaptic excitability (9). The aim of the current study was to unravel the physiological role of PFN2a in regulating dendrite morphology and spine stability of mature pyramidal neurons. We used a loss-of-function approach inducing RNAimediated knockdown of PFN2a in hippocampal neurons. Furthermore, we investigated whether PFN2a might be involved in the regulation of actin dynamics downstream of known effectors of neuronal morphology, su...

SummaryInhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.

Background: Multiple profilin isoforms exist in mammals; at least four are expressed in the mammalian testis. The testis-specific isoforms profilin-3 (PFN3) and profilin-4 (PFN4) may have specialized roles in spermatogenic cells which are distinct from known functions fulfilled by the "somatic" profilins, profilin-1 (PFN1) and profilin-2 (PFN2).