The role of transglutaminase 2 in mediating glial cell function and pathophysiology in the central nervous system.

The ubiquitously expressed transglutaminase 2 (TG2) has diverse functions in virtually all cell types, with its role depending not only on cell type, but also on specific subcellular localization. In the central nervous system (CNS) different types of glial cells, such as astrocytes, microglia, and oligodendrocytes and their precursor cells (OPCs), play pivotal supportive functions. This review is focused on what is currently known about the role of TG2 in each type of glial cell, in the context of normal function and pathophysiology. For example, astrocytic TG2 facilitates their migration and proliferation, but hinders their ability to protect neurons after CNS injury. The review also examines the interactions between glial cell types, and how TG2 in one cell type may affect another, as well as implications for specific TG2 populations as therapeutic targets in CNS pathology.

Neonatal pain and stress disrupts later-life pavlovian fear conditioning and sensory function in rats: Evidence for a two-hit model.

Early life trauma has been linked to increased risks for anxiety, depression, and chronic pain. We used rodent models of acute and inflammatory neonatal pain to explore effects on fear conditioning and somatosensory function. Hindpaw needle pricks or handling on postnatal days (PNDs) 1-7 caused lasting impacts on affective and somatosensory function when assessed at later ages, PNDs 24 (postweaning), 45 (adolescence), or 66 (adulthood). First, auditory, but not contextual, freezing was mildly disrupted regardless of age. Second, a profound postfear conditioning tactile hypersensitivity was observed in neonatally stressed, postweaning rats. In the absence of fear conditioning, the mechanical hypersensitivity was not observed, consistent with a two-hit model of psychopathology. Injections of 2% α-carrageenan did not have the same lasting impact but was slightly protective against observed effects of neonatal vehicle injections. Basal and elicited corticosterone levels postweaning were not altered by neonatal pain or handling. These data demonstrate that neonatal adversity can have lasting impacts on affective and somatosensory function that differs regardless of age.

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury.

Following CNS injury, astrocytes become "reactive" and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/- TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

The Effects of Acute Neonatal Pain on Expression of Corticotropin-Releasing Hormone and Juvenile Anxiety in a Rodent Model.

Premature infants in the neonatal intensive care unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects' left plantar paw surface which occurred four times daily during the first week of life [postnatal day (PND)1-PND7]. Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND6) and fluorescent in situ hybridization (FISH) for corticotropin-releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND24 and PND25) and underwent innate anxiety testing utilizing an elevated plus maze (EPM) protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage.