Improved neuron protection following cortical injury in the absence of Semaphorin4B

Abstract

Injury to the central nervous system induces neuronal cell death and astrogliosis, an astrocyte-mediated response that has both a beneficial and detrimental impact on surrounding neuronal cells. The circumstance however, in which astrogliosis improves neuronal survival after an injury is not fully characterized. We have recently shown that Semaphorin4B (Sema4B) in the cortex is mostly expressed by astrocytes, and in its absence, astrocyte activation after an injury is altered. Here we find that in Sema4B knockout mice, neuronal cell death is reduced; as a result, more neurons survive near the injury site. Sema4B protein applied directly to neurons does not affect neuronal survival. In contrast, survival of wild-type neurons is increased when plated on glial culture isolated from the Sema4B knockout mice, as compared to Sema4B heterozygous cultures. Furthermore, this increased survival is also observed with conditioned medium collected from glial cultures of Sema4B knockout mice compared to heterozygous mice. This indicates that the increased survival is glial cell-dependent and mediated by a secreted factor(s). Together, our results imply that following injury, the lack of Sema4B expression in glial cells improves neuronal survival either as a result of reduced toxic factors, or perhaps increased survival factors under these conditions.

Astrocyte-to-microglia communication via Sema4B-Plexin-B2 modulates injury-induced reactivity of microglia

“…We have previously shown that Sema4B is expressed by cortical astrocytes and in its absence, the astrocyte activation profile is altered, and proliferation is reduced following cortical injury (11). We also showed that neuronal cell death 24h and 72h after a stab wound injury is reduced in these Sema4B knockout mice (12). These results imply that Sema4B affects the central nervous system’s response to injury.…”

“…Interestingly, microglial/macrophage reactivity is attenuated, although less than what we observed in Sema4B knockout mice. Since in the absence of Sema4B, neurons are more protected after injury (12), we tested if this is the case in Cx3cr1creER:PlexinB2 fl/fl mice as well. For this, we stained tissues using slices with FJC 24h after injury.…”

“…It seems that Sema4B may play a similar role. First, we have recently shown that in cortical injury neuronal cell death is reduced in the absence of Sema4B (12). Moreover, here we show that in the absence of Sema4B in mice, activation of microglial cells attenuated.…”

Astrocyte-to-microglia communication via Sema4B-Plexin-B2 modulates injury-induced reactivity of microglia

“…We have previously shown that Sema4B is expressed by cortical astrocytes and in its absence, the astrocyte reactivity profile is altered, and proliferation is reduced following cortical injury ( 10 ). We also showed that neuronal cell death 24 h and 72 h after a stab wound injury is reduced in these Sema4B −/− mice ( 11 ). These results imply that Sema4B affects the central nervous system’s response to injury.…”

“…Together, both the morphological changes and Tmem119 expression level are consistent with reduced reactivity of microglia in PlexinB2 fl/fl . Since in the absence of Sema4B , neurons are more protected after injury ( 11 ), we evaluated whether this is also the case in Cx3cr1creER:PlexinB2 fl/fl mice. We stained tissue slices with Fluoro-Jade C (FJC) 24 h after injury ( Fig.…”