Repetitive Diffuse Mild Traumatic Brain Injury Causes an Atypical Astrocyte Response and Spontaneous Recurrent Seizures

Abstract

Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/ concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human TBI patients. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI.

Questions and (some) answers on reactive astrocytes

“…Moreover, reactive astrocytes may lose some of their defining functional features like input resistance, membrane currents, and gapjunction coupling, as described in human brains and in a mouse model of sclerotic mesial temporal lobe epilepsy . They may also express lower levels of key astrocyte proteins, as discussed earlier (Sections 4 and 9), and as shown after mild repetitive TBI with loss of GLT1, GS, KIR4.1, and even GFAP (Shandra et al, 2019). This will complicate their identification as astrocytes.…”

“…Some genes associated with important astrocyte functions like the potassium channel KIR4.1 [Kcnj10, (Nwaobi, Cuddapah, Patterson, Randolph, & Olsen, 2016)], the glutamate transporter GLT1 (Slc1a2), or glutamine synthase GS [GluI, (Sheldon & Robinson, 2007)] are repeatedly reported as down regulated in disease. Likewise, reduced expression of several homeostatic astrocyte genes is reported in mouse models of SWI and TBI (Shandra et al, 2019) (see also Section 10), but there is no established list of genes down-regulated in reactive astrocytes across multiple diseases. Overall, the significant phenotypic alterations observed in reactive astrocytes involve large-scale transcriptome modifications and functional changes (see Section 8).…”

Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

“…A continuing growth of supporting evidence implicates astrocytes as active participants in the multicellular networked responses potentially underlying, resolving, or exacerbating CNS diseases and injury [20,21]. As a variety of roles of astrocytes within the disease or injury milieu are being identified, it is becoming clearer that astrocyte response is rather heterogeneous [17,20,[22][23][24], with implications pointing toward a diversity of graded responses [25]. Critically, among these responses are multiple domains encompassing inflammatory response, tissue protection, vascular response, as well as neuronal functionality [26].…”

Drebrin mediates scar formation and astrocyte reactivity during brain injury by inducing RAB8 tubular endosomes

“…We then asked if this defective glial scar development affects surrounding neurons. Loss of NeuN indicates degenerating neurons (Alekseeva et al, 2015), and its translocation from the nucleus to the cytosol identifies neurons exhibiting an initial stress response to pathologies (Lucas et al, 2014;Shandra et al, 2019;Wang et al, 2015;Wiley et al, 2016). Following stab injury, WT brains consistently maintained NeuN in the neuronal nuclei irrespective of their position relative to the injury site.…”