Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau−/−) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau−/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.

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We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

It is generally accepted that the cerebellum is particularly vulnerable to ischaemic injury, and this may contribute to the high mortality arising from posterior circulation strokes. However, this has not been systematically examined in an animal model. This study compared the development and resolution of matched photothrombotic microvascular infarcts in the cerebellar and cerebral cortices in adult 129/SvEv mice of both sexes. The photothrombotic lesions were made using tail vein injection of Rose Bengal with a 532 nm laser projected onto a 2 mm diameter aperture over the target region of the brain (with skull thinning). Infarct size was then imaged histologically following 2 h to 30-day survival using serial reconstruction of haematoxylin and eosin stained cryosections. This was complemented with immunohistochemistry for neuron and glial markers. At 2 h post-injury, the cerebellar infarct volume averaged ~ 2.7 times that of the cerebral cortex infarcts. Infarct volume reached maximum in the cerebellum in a quarter of the time (24 h) taken in the cerebral cortex (4 days). Remodelling resolved the infarcts within a month, leaving significantly larger residual injury volume in the cerebellum. The death of neurons in the core lesion at 2 h was confirmed by NeuN and Calbindin immunofluorescence, alongside activation of astrocytes and microglia. The latter persisted in the region within and surrounding the residual infarct at 30 days. This comparison of acute focal ischaemic injuries in cerebellar and cerebral cortices provides direct confirmation of exacerbation of neuropathology and faster kinetics in the cerebellum.

Inflammation plays an important role in the pathophysiology of neonatal hypoxic-ischemic (HI) brain injury. Studies have shown that hypoxic preconditioning (HP) can ameliorate brain damage, but its effects on inflammation remain unknown. Postnatal day 6 (P6), Sprague-Dawley rats were divided into normoxia and hypoxia (8% oxygen, 3h) groups. On P7, some pups underwent a right carotid artery occlusion followed by hypoxia (8% oxygen, 3h) while under 1.5% isofluorane anesthesia and the remaining pups underwent sham surgery without occlusion. Animals were sacrificed 5 days later and fixed tissue was used to examine changes in neurons, astrocytes, and microglia in the cortex. Fresh tissue was collected to determine cortical levels of proinflammatory cytokines using ELISA. There was a significant loss in the number of NeuN positive cells in the cortex following HI injury, which was improved when HP was given prior to HI. There was an increase in cortical area of astrocyte staining after HI injury compared to control. HP before HI was able to reduce area of GFAP staining back to control levels. HI caused a large increase in the number of activated microglia compared to control and HP was able to significantly reduce this, although not back to control levels. HP alone increased microglial activation. Interleukin-1β levels were increased in the cortex 5 days after HI, but HP was not able to significantly reduce this change. The neuroprotective effects of HP appear to be mediated by affecting cellular inflammatory processes in the brain following HI injury.