Astrocytic role of Thy-1 induced inhibition of axonal sprouting.
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ABSTRACT:
SUBMITTER: Whiteman ST
PROVIDER: S-EPMC8224143 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Astrocytic role of Thy-1 induced inhibition of axonal sprouting.
Whiteman Sara T ST Askvig Jason M JM
Neural regeneration research 20210601 6
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Project description:Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP response element-binding protein (CREB), which controls neuronal excitability and growth responses. CREB gain of function enhances learning and allocates neurons into memory engrams. CREB also controls recovery after stroke. PDE inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair, and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct, and functional disconnection of neuronal networks. PDE2A inhibition enhances functional recovery, increases axonal projections in peri-infarct cortex, and, through two-photon in vivo imaging, enhances the functional connectivity of motor system excitatory neurons. PDE2A inhibition after stroke does not have an effect on other aspects of tissue repair, such as angiogenesis, gliogenesis, neurogenesis, and inflammatory responses. These data suggest that PDE2A inhibition is an effective therapeutic approach for stroke recovery in the rodent and that it simultaneously enhances connectivity in peri-infarct neuronal populations.SIGNIFICANCE STATEMENT Inhibition of PDE2A enhances motor recovery, axonal projections, and functional connectivity of neurons in peri-infarct tissue. This represents an avenue for a pharmacological therapy for stroke recovery.
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Project description:GDF10 controls a unique transcriptome, which coordinately regulates several molecular signaling systems that provide insights into how this molecule induces a neuronal growth state and is distinct from other developmental and adult plasticity phenotypes.
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Project description:One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory?somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory?somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise?inducing temporary threshold shift and were subsequently divided into tinnitus and non?tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub?groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth?associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, ??thalassemia/mental retardation syndrome X?linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine?rich repeat and immunoglobulin domain?containing 1, were measured by western blot analyses. Compared to the non?tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post?exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.
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Project description:Stroke is an age-related disease. Recovery after stroke is associated with axonal sprouting in cortex adjacent to the infarct. The molecular program that induces a mature cortical neuron to sprout a new connection after stroke is not known. We selectively isolated neurons that sprout a new connection in cortex after stroke and compared their whole-genome expression profile to that of adjacent, non-sprouting neurons. This 'sprouting transcriptome' identified a neuronal growth program that consists of growth factor, cell adhesion, axonal guidance and cytoskeletal modifying molecules that differed by age and time point. Gain and loss of function in three distinct functional classes showed new roles for these proteins in epigenetic regulation of axonal sprouting, growth factor-dependent survival of neurons and, in the aged mouse, paradoxical upregulation of myelin and ephrin receptors in sprouting neurons. This neuronal growth program may provide new therapeutic targets and suggest mechanisms for age-related differences in functional recovery.
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Project description:Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.
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Project description:In addition to neuroprotective strategies, neuroregenerative processes could provide targets for stroke recovery. However, the upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) impedes innate regenerative efforts. Here, we examine the regulatory role of PTPσ (a major proteoglycan receptor) in dampening post-stroke recovery. Use of a receptor modulatory peptide (ISP) or Ptprs gene deletion leads to increased neurite outgrowth and enhanced NSCs migration upon inhibitory CSPG substrates. Post-stroke ISP treatment results in increased axonal sprouting as well as neuroblast migration deeply into the lesion scar with a transcriptional signature reflective of repair. Lastly, peptide treatment post-stroke (initiated acutely or more chronically at 7 days) results in improved behavioral recovery in both motor and cognitive functions. Therefore, we propose that CSPGs induced by stroke play a predominant role in the regulation of neural repair and that blocking CSPG signaling pathways will lead to enhanced neurorepair and functional recovery in stroke.
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Project description:Neurodegenerative lesions induce sprouting of new collaterals from surviving axons, but the extent to which this form of axonal remodelling alters brain functional structure remains unclear. To understand how collateral sprouting proceeds in the adult brain, we imaged post-lesion sprouting of cerebellar climbing fibres (CFs) in mice using in vivo time-lapse microscopy. Here we show that newly sprouted CF collaterals innervate multiple Purkinje cells (PCs) over several months, with most innervations emerging at 3-4 weeks post lesion. Simultaneous imaging of cerebellar functional structure reveals that surviving CFs similarly innervate functionally relevant and non-relevant PCs, but have more synaptic area on PCs near the collateral origin than on distant PCs. These results suggest that newly sprouted axon collaterals do not preferentially innervate functionally relevant postsynaptic targets. Nonetheless, the spatial gradient of collateral innervation might help to loosely maintain functional synaptic circuits if functionally relevant neurons are clustered in the lesioned area.
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Project description:The Brain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity. In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting-an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning occurring after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.
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Project description:Thy-1 is a membrane glycoprotein suggested to stabilize or inhibit growth of neuronal processes. However, its precise function has remained obscure, because its endogenous ligand is unknown. We previously showed that Thy-1 binds directly to ?(V)?(3) integrin in trans eliciting responses in astrocytes. Nonetheless, whether ?(V)?(3) integrin might also serve as a Thy-1-ligand triggering a neuronal response has not been explored. Thus, utilizing primary neurons and a neuron-derived cell line CAD, Thy-1-mediated effects of ?(V)?(3) integrin on growth and retraction of neuronal processes were tested. In astrocyte-neuron co-cultures, endogenous ?(V)?(3) integrin restricted neurite outgrowth. Likewise, ?(V)?(3)-Fc was sufficient to suppress neurite extension in Thy-1(+), but not in Thy-1(-) CAD cells. In differentiating primary neurons exposed to ?(V)?(3)-Fc, fewer and shorter dendrites were detected. This effect was abolished by cleavage of Thy-1 from the neuronal surface using phosphoinositide-specific phospholipase C (PI-PLC). Moreover, ?(V)?(3)-Fc also induced retraction of already extended Thy-1(+)-axon-like neurites in differentiated CAD cells as well as of axonal terminals in differentiated primary neurons. Axonal retraction occurred when redistribution and clustering of Thy-1 molecules in the plasma membrane was induced by ?(V)?(3) integrin. Binding of ?(V)?(3)-Fc was detected in Thy-1 clusters during axon retraction of primary neurons. Moreover, ?(V)?(3)-Fc-induced Thy-1 clustering correlated in time and space with redistribution and inactivation of Src kinase. Thus, our data indicates that ?(V)?(3) integrin is a ligand for Thy-1 that upon binding not only restricts the growth of neurites, but also induces retraction of already existing processes by inducing Thy-1 clustering. We propose that these events participate in bi-directional astrocyte-neuron communication relevant to axonal repair after neuronal damage.
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Project description:Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and differentiation factor 10 (GDF10) is induced in peri-infarct neurons in mice, non-human primates and humans. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGF?RI and TGF?RII signaling. Using pharmacogenetic gain- and loss-of-function studies, we found that GDF10 produced axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocked axonal sprouting and reduced recovery. RNA sequencing from peri-infarct cortical neurons revealed that GDF10 downregulated PTEN, upregulated PI3 kinase signaling and induced specific axonal guidance molecules. Using unsupervised genome-wide association analysis of the GDF10 transcriptome, we found that it was not related to neurodevelopment, but may partially overlap with other CNS injury patterns. Thus, GDF10 is a stroke-induced signal for axonal sprouting and functional recovery.
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