The mechanisms underpinning concussion, traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE) are poorly understood. Using neuropathological analyses of brains from teenage athletes, a new mouse model of concussive impact injury, and computational simulations, Tagge et al. show that head injuries can induce TBI and early CTE pathologies independent of concussion.

SNAP-25 exists as two developmentally regulated alternatively spliced isoforms, SNAP-25a and SNAP-25b. We explored the function of SNAP-25a and SNAP-25b at Schaffer collateral-CA1 synapses in hippocampus using 4-week-old wild-type (WT) and SNAP-25b-deficient (MT) mice. Characterizing the protein expression of individual SNAP-25 isoforms revealed that WT females had higher levels of SNAP-25a than WT males, suggesting a sex-dependent delay of the alternative splicing switch from SNAP-25a to SNAP-25b. MT mice expressed normal levels of total SNAP-25, Syntaxin 1A and SNAP-47 in the hippocampus, but females expressed lower levels of VAMP2. Electrophysiological recordings in in vitro hippocampal slices revealed significantly reduced magnitude of LTP in MT mice. We also found reduction in paired-pulse facilitation after induction of LTP in WT males, but not in WT females, possibly related to the difference in SNAP-25a/SNAP-25b ratios, suggesting that the splicing switch may play a sex-specific role in LTP-associated increases in presynaptic release probability. Basal synaptic transmission measured in input-output relations revealed that the ability to discriminate between the intensity of presynaptic stimuli was affected in SNAP-25b-deficient mice. Learning in a behavioural paradigm of active-avoidance was impaired in MT mice, strengthening the conclusion that SNAP-25b is important for cognitive performance by altering activity-dependent synaptic plasticity.

Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor ␣ (TR␣) and TR␤. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TR␣ expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TR␣. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.