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Traumatic brain injury (TBI) is a frequent consequence of vehicle, sport and war related injuries. More than 90% of TBI patients suffer mild injury (mTBI). However, the pathologies underlying the disease are poorly understood and treatment modalities are limited. We report here that in mice, the potent PKC activator bryostatin1 protects against mTBI induced learning and memory deficits and reduction in pre-synaptic synaptophysin and post-synaptic spinophylin immunostaining. An effective treatment has to start within the first 8 h after injury, and includes 5× i.p. injections over a period of 14 days. The treatment is dose dependent. Exploring the effects of the repeated bryostatin1 treatment on the processing of the amyloid precursor protein, we found that the treatment induced an increase in the putative α-secretase ADAM10 and a reduction in β-secretase activities. Both these effects could contribute towards a reduction in β-amyloid production. These results suggest that bryostatin1 protects against mTBI cognitive and synaptic sequela by rescuing synapses, which is possibly mediated by an increase in ADAM10 and a decrease in BACE1 activity. Since bryostatin1 has already been extensively used in clinical trials as an anti-cancer drug, its potential as a remedy for the short- and long-term TBI sequelae is quite promising.

MHC class I molecules (MHC-I) have been implicated in nervous system development in the mouse. In this study we present evidence for the interaction of MHC-I with the NK cell receptor Ly49 in primary cortical neuronal cultures. We show that MHC-I and Ly49 are expressed on neuronal soma and axon surfaces, with Ly49 also present on dendrites. Anti-MHC-I Abs reduce synapsin-I expression and enhance neurite outgrowth and neuronal death. Conversely, anti-Ly49 mAbs increase synapsin-I expression, reduce neurite outgrowth, and promote neuron viability. Because we show that Ly49 genes are selectively expressed in the adult brain, these findings suggest an unsuspected role for the MHC-I-Ly49 interaction in the development and function of the brain.

Interpretation of the cellular and molecular pathogenic basis of post-minimal traumatic brain injury is a significant clinical and scientific problem, especially due to the high prevalence of motor vehicle--and other accidents. Pathogenetic brain mechanisms following traumatic impact are usually investigated by using models of severe or moderate trauma. Apoptotic neuronal degeneration after notable brain trauma is a well-known phenomenon, but the source of its activation is not clear, especially after mild, subclinical brain trauma. In the present study, we used a closed head weight-drop model to induce minimal brain injury in mice. Pellets of 5, 10, 15, 20, 25 and 30 g were dropped on the right side of mice's head kept under light ether anesthesia. No abnormal behavioral or neurophysiological changes were seen following the head trauma. Morphological assessment was done 72 h after the traumatic impact using TUNEL assay and silver staining. We found gradual increase of TUNEL-positive and silver-impregnated cells number in different cortical and hippocampal regions of both injured and contralateral hemispheres. The threshold of traumatic impact that caused a significant activation was 10-15 g pellets (evident by silver staining), and 15-20 g for apoptosis. The most sensitive zones for trauma were anterior cingulate cortex and CA3 area of hippocampus. No bilateral hemispheric differences were found. Our results demonstrate that even closed head minimal traumatic brain injury can cause diffused neuronal damage and apoptosis. This results correlate well with cognitive and behavioral deficits described for mice suffering similar mTBI and can also explain the wide variety of mental disturbances described for post-concussion syndrome in patients who suffered mild head injury.

Victims of minor traumatic brain injury (mTBI) can show long lasting cognitive, emotional and concentration difficulties, amnesia, depression, apathy and anxiety. The symptoms are generally known as a post-concussive syndrome without clear morphological brain defects. Endogenous opiates are released after impact to the brain, suggesting they may play a role in TBI pathophysiology. Furthermore, the administration of opiates to the brain of injured animals has been shown to affect the injury, induce cellular changes and also have protective qualities for neurological impairments. Here, we examined the protective properties of the opiate morphine on cognitive performances following minimal brain injury in mice. For this purpose, we have used our non-invasive closed-head weight drop model in mice, which closely mimics real life mTBI and examined mice performance in the Morris water maze. Our procedure did not cause visible structural or neurological damage to the mice. A single morphine injection administrated immediately after the induction of minimal TBI protected the injured mice from cognitive impairment, checked 30, 60 and 90 days post injury. However, mice injected with morphine that were examined 7 days after the injury did not show better performance than the saline injected mice. Our results indicate that morphine has long but not short-term effects on the cognitive ability of brain-injured mice. Although the exact nature of opioid neuroprotection is still unknown, its elucidation may lead to the much-needed treatment for traumatic brain injury.

Plaques found in the brains of patients suffering from Alzheimer's disease (AD) mainly consist of beta-amyloid (Abeta), which is produced by sequential cleaving of amyloid precursor protein (APP) by two proteolytic enzymes, beta- and gamma-secretases. Any change in the fine balance between these enzymes and their substrate may contribute to the etio-pathogenesis of AD. Indeed, the protein level and enzymatic activity of beta-secretase (BACE), but not its mRNA level, were found elevated in brain areas of AD patients who suffer a high load of Abeta plaque formation. Similarly, increased BACE activity but no mRNA change was observed in a transgenic mouse model of AD, tg2576, in which over expression of the Swedish mutated human APP leads to Abeta plaque formation and learning deficits. Based on the recent demonstration of four BACE splice variants with different enzymatic activity, the discrepancy between BACE activity and mRNA expression may be explained by the altered BACE alternative splicing. To test this hypothesis, we studied the expression of all BACE splice variants in different brain areas of tg2576 mice at age of 4 months and 1 year old. We found developmental and regional differences between wild-type and tg2576 mice. Our results indicate that over expression of APP in tg2576 mice leads to the altered alternative splicing of BACE and the increase of its enzymatically more active splice variant (I-501).

Improvised explosive devices (IEDs) are one of the main causes for casualties among civilians and military personnel in the present war against terror. Mild traumatic brain injury from IEDs induces various degrees of cognitive, emotional and behavioral disturbances but knowledge of the exact brain pathophysiology following exposure to blast is poorly understood. The study was aimed at establishing a murine model for a mild BI-TBI that isolates low-level blast pressure effects to the brain without systemic injuries. An open-field explosives detonation was used to replicate, as closely as possible, low-level blast trauma in the battlefield or at a terror-attack site. No alterations in basic neurological assessment or brain gross pathology were found acutely in the blast-exposed mice. At 7 days post blast, cognitive and behavioral tests revealed significantly decreased performance at both 4 and 7 meters distance from the blast (5.5 and 2.5 PSI, respectively). At 30 days post-blast, clear differences were found in animals at both distances in the object recognition test, and in the 7 m group in the Y maze test. Using MRI, T1 weighted images showed an increased BBB permeability one month post-blast. DTI analysis showed an increase in fractional anisotropy (FA) and a decrease in radial diffusivity. These changes correlated with sites of up-regulation of manganese superoxide dismutase 2 in neurons and CXC-motif chemokine receptor 3 around blood vessels in fiber tracts. These results may represent brain axonal and myelin abnormalities. Cellular and biochemical studies are underway in order to further correlate the blast-induced cognitive and behavioral changes and to identify possible underlying mechanisms that may help develop treatment- and neuroprotective modalities.

Victims of minor traumatic brain injury (mTBI), who show no clear morphological brain defects, frequently manifest cognitive, behavioral and emotional difficulties that can be long-lasting. In this paper we present a modified weight drop model used to deliver a closed head minimal traumatic brain injury to mice, which closely mimics real-life injuries and the symptoms observed in mTBI patients. Our choice of impact force does not produce structural damage to the brain and its surrounding tissue (as examined by MRI), any skull fracture, no edema and no evident damage to the blood-brain barrier (BBB). Moreover, our mTBI mice show no abnormal behavior on recovering from the weight drop, or any change in other brain functions such as reflexes, balance, exploration, strength, locomotor activity and swim speed. Since our mTBI model does not produce neurological, motor or sensory damage to the mice, it allows the direct evaluation of mTBI sequelae on the mice behavior and cognitive abilities. Using a variety of cognitive and behavioral tests (Morris water maze, staircase test, passive avoidance test, water T-maze, hot palate, elevated plus maze and forced swimming test) we assessed the short- and long-term sequelae induced by our model. Our results indicate that our closed head mTBI cause profound and long-lasting, irreversible learning and memory impairments, accompanied by a depressive-like behavior in mice that are evident even 90 days post injury. Our results indicate that the closed head mTBI model presented here may be useful in the development of novel therapeutic approaches, such as neuroprotective agents, for mTBI.

Mild traumatic brain injury (mTBI) is characterized by diffused symptoms, which when combined are called "post-concussion syndrome". Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive neurosteroid. Previously, we have reported that closed head mTBI causes long lasting cognitive deficits and depressive-like behavior. In the present study we describe the effects of DHEAS on the behavior of mice that suffered closed head mTBI. Following the induction of mTBI, mice were treated once a week with DHEAS (s.c. 20 mg/kg) and their performance in the passive avoidance test and the forced swimming test (FST) were evaluated 7, 30, 60 and 90 days post-injury. The most important interactions were between injury and injection (passive avoidance; p

Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mice's ability to perform the Morris water maze. The mice suffered profound long-lasting learning and memory deficits that were force- and time-dependent. Although the injured mice could acquire the task, they could not improve their initial escape latency by more than 50%, while normal mice improved by up to 450% (P