Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus.

The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation.

Repetitive Transcranial Magnetic Stimulation Alleviates Neurological Deficits After Cerebral Ischemia Through Interaction Between RACK1 and BDNF exon IV by the Phosphorylation-Dependent Factor MeCP2.

Repetitive transcranial magnetic stimulation (rTMS) is acknowledged as a form of neurostimulation, especially for functional recovery. The foundational knowledge of molecular mechanism is limited regarding its role in cerebral ischemia, for which the present study was designed. Primary neurons were treated with oxygen-glucose deprivation (OGD) and repetitive magnetic stimulation (rMS), in which brain-derived neurotrophic factor (BDNF) and transcription of BDNF exons were examined. Then, adenovirus vectors carrying siRACK1 sequence were delivered to primary neurons, followed by detection of the transcription of BDNF exons and the extent of methyl CpG binding protein 2 (MeCP2) phosphorylation. Results showed that BDNF and the transcription of BDNF exons were upregulated by rMS and OGD treatment, but decreased by extra treatment of RACK1 siRNA. Then, the mechanism investigations demonstrated that rMS increased the extent of MeCP2 phosphorylation to promote the interaction between RACK1 and BDNF exon IV. The aforementioned findings were further confirmed in vivo in middle cerebral artery occlusion (MCAO)-induced rat models, as indicated by improved neurological functions and reduced area of cerebral infarction. The study offers potential evidence for improvement of neurological deficits, highlighting the important role of rTMS for treatment of cerebral ischemia.

Acetylation of PGC1α by Histone Deacetylase 1 Downregulation Is Implicated in Radiation-Induced Senescence of Brain Endothelial Cells.

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated ß-galactosidase-positive cells and a decrease in cell proliferation and adenosine triphosphate production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated ß-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α protein levels were not decreased, PGC1 acetylation was increased by ionizing radiation treatment and aging. Histone deacetylase 1 (HDAC1) expression was decreased by ionizing radiation treatment and aging, and downregulation of HDAC1 induced acetylation of PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α is induced by DNA damage agents such as ionizing radiation, which deregulates mitochondrial mechanisms and metabolism, resulting in acceleration of radiation-induced senescence. Therefore, acetylation of PGC1α may be a cause of brain disorders and has the potential to serve as a therapeutic target for radiation-induced senescence after radiation cancer therapy.

Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Loss of neurons in specific brain regions has been found in depression and schizophrenia, and this chapter summarizes the findings of altered neurotrophins in animal models of those two disorders under baseline condition and following antidepressive and antipsychotic treatments. In a model of depression (Flinders sensitive line/Flinders resistant line; FSL/FRL rats), increased NGF and BDNF concentrations were found in frontal cortex of female, and in occipital cortex of male 'depressed' FSL compared to FRL control rats. Using the same model, the effects of electroconvulsive stimuli (ECS) and chronic lithium treatment on brain NGF, BDNF and glial cell line-derived neurotrophic factors were investigated. ECS and lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. ECS mimic the effects of electroconvulsive therapy (ECT) that is an effective treatment for depression and also schizophrenia. Since NGF and BDNF may also be changed in the CNS of animal models of schizophrenia, we investigated whether treatment with antipsychotic drugs (haloperidol, risperidone, and olanzapine) affects the constitutive levels of NGF and BDNF in the CNS. Both typical and atypical antipsychotic drugs altered the regional brain levels of NGF and BDNF. Other studies also demonstrated that these drugs differentially altered neurotrophin mRNAs. Overall, these studies indicate that alteration of brain level of NGF and BDNF could constitute part of the biochemical alterations induced by antipsychotic drugs.

Effects of X-irradiation on nerve growth factor in the developing mouse brain.

The involvement of neurotrophins after radiation injury during brain development were studied in pregnant mice (C 57/B1) exposed on gestation day 15 to X-ray doses of 0.02-2 Gy. Nerve growth factor protein (NGF) and different cholinergic markers were investigated on postnatal day 1 (P1) and day 21 (P21); in situ hybridization with brain-derived neurotrophic factor (BDNF) and trkC (receptor serving to bind neurotrophin-3) probes was investigated on P21 in cortex, hippocampus, septum and cerebellum. The level of NGF protein was increased in irradiated forebrain on P1 in a dose-related manner. However, on P21 the NGF protein dropped down below the control levels in irradiated hippocampus and cerebellum. The response of acetylcholine esterase (AChE) activity in cerebellum at P21 was correlated with the changes in the amount of NGF. The intensity of cell labelling with trkC probe decreased after irradiation in the region of the hippocampus at P21, especially in dentate gyrus. The expression of BDNF mRNA was increased at P21 by low doses of irradiation (0.02-1 Gy) but was decreased by a high dose (2 Gy) in the same area. Thus, the radiation induced an alteration of neurotrophins, and the changes varied depending on the dose or time after irradiation. Such alterations in the pattern of growth factor production may modulate the response of cells to radiation. Furthermore, NGF protein levels and the expression of BDNF and trkC mRNA were affected by radiation doses as low as 0.02 Gy, indicating that during development the neurotrophins and their receptors are very sensitive to radiation.

Effects of altered levels of extracellular superoxide dismutase and irradiation on hippocampal neurogenesis in female mice.

PURPOSE: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. METHODS AND MATERIALS: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, and long-term survival of newborn neurons were determined. RESULTS: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC-SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. CONCLUSION: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted.

Expression of TrkB receptors in developing visual cortex is not regulated by light.

1. Neurotrophins are very good candidates which relate electrical activity to molecular changes in activity-dependent phenomena. They exert their action through binding to specific tyrosine-kinase receptors: Trk receptors. It is important to consider Trk distribution in order to understand better the role of neurotrophins in the Central Nervous System (CNS). We focused our attention on brain-derived neurotrophic factor (BDNF) Trk receptors (TrkB) during development of the rat visual cortex, since this neurotrophin has been shown to play an important role in visual system development and plasticity. 2. We investigated the full length form of TrkB receptors considering both its total amount and its cellular distribution. To address this issue we used an antibody that recognizes the full length form of TrkB and we used it both in Western blot and immunohistochemistry. 3. We found that the expression of TrkB receptor increases during development, but that there is no effect on visual experience, since dark-reared animals show the same protein level and pattern of TrkB expression compared to age-matched, normally reared controls.