Developmental neurobiology
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis due to the selective death of motor neurons of unknown causes. Increasing evidence indicates that Wnt signaling is altered in ALS. In this study, we focused on two non-canonical Wnt signaling components, atypical PKC (aPKC) and a Wnt receptor, Ryk, in a mouse model of ALS, SOD1 (G93A). aPKC mediates Wnt signaling to regulate growth cone guidance, axon differentiation and cell survival. ⋯ These results suggest that aPKC may be sequestered in SOD1 aggregates, impairing its ability to protect motor neurons from death. Ryk expression was also increased in the motor neurons and the white matter in the ventral lumbar spinal cord of mutant SOD1 mice with a peak at early stage. These observations indicate that Wnt/aPKC and Wnt/Ryk signaling are altered in SOD1 (G93A) mice, suggesting that changed Wnt signaling may contribute to neurodegeneration in ALS.
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Local protein synthesis has been demonstrated in the peripheral processes of sensory primary afferents and is thought to contribute to the maintenance of the neuron, to neuronal plasticity following injury and also to regeneration of the axon after damage to the nerve. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, integrates a variety of cues that regulate cellular homeostasis and is thought to play a key role in coordinating the neuronal response to environmental challenges. ⋯ Inhibition of mTOR complex 1 (mTORC1) has shown that while the acute response to noxious stimulation is unaffected, more complex aspects of pain processing including the setting up and maintenance of chronic pain states can be disrupted suggesting a route for the generation of new drugs for the control of chronic pain. Given the role of mTORC1 in cellular homeostasis, it seems that systemic changes in the physiological state of the body such as occur during illness are likely to modulate the sensitivity of peripheral sensory afferents through mTORC1 signaling pathways.
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Review
Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.
In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, increased toxoplasma antibody, genital-reproductive infections, rubella, and other pathogens are associated with schizophrenia. ⋯ Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions.
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Review
The ever-changing brain: cellular and molecular mechanisms for the effects of stressful experiences.
The adult brain is capable of considerable structural and functional plasticity and the study of hormone actions in brain has contributed to our understanding of this important phenomenon. In particular, stress and stress-related hormones such as glucocorticoids and mineralocorticoids play a key role in the ability of acute and chronic stress to cause reversible remodeling of neuronal connections in the hippocampus, prefrontal cortex, and amygdala. ⋯ The result is a dynamic brain architecture that can be modified by experience. Under this view, the role of pharmaceutical agents, such as antidepressants, is to facilitate such plasticity that must also be guided by experiences.
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Of the nearly 3 million Americans diagnosed with epilepsy, approximately 30% are unresponsive to current medications. Recent data has shown that early postnatal transplantation of interneuronal precursor cells increases GABAergic inhibition in the host brain and dramatically suppresses seizure activity in epileptic mice. In this review, we will highlight findings from seizure-prone mice and humans that demonstrate the link between dysfunctional GABAergic inhibition and hyperexcitability. ⋯ A wealth of literature showing a causal link between reduced GABA-mediated inhibition and seizures has directed our efforts to recover the loss of inhibition via transplantation of interneuronal precursors. Numerous related studies have explored the anticonvulsant potential of cell grafts derived from a variety of brain regions, yet the mechanism underlying the effect of such heterogeneous cell transplants is unknown. In discussing our recent findings and placing them in context with what is known about epilepsy, and how related transplant approaches have progressed, we hope to initiate a frank discussion of the best path toward the translation of this approach to patients with intractable forms of epilepsy.