Vol 11, N°3 Neurotoxicity and Neuroprotection
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I n  t h i s  i s s u e... Our brains are incredibly plastic—able to learn, remem- ber, and change in the service of adaptation. As such, unlike what many of us were taught, the brain is not a collection of structurally invariant components, but rather is a dynamic organ, both structurally and functionally. And just as alterations in gene expression and synaptic connectivity and strength are critical to learning and stress adaptation, so can disturbances in brain plasticity result in behavioral disturbances and, indeed, classical psychiatric disorders. This issue of Dialogues in Clinical Neuroscience discusses neuroprotection and neurotoxic- ity, not as trivial academic conceits, but as processes that can now be shown to underpin a variety of psychiatric disorders and that may offer future directions for novel therapeutics. In the State of the art opening article (p 239), Ron Duman summarizes a burgeoning literature demonstrat- ing the structural and cellular effects of stressors and depression as well as the mechanisms underlying these effects. An impressively consistent story implicates oppos- ing effects of stress and depression versus antidepressant therapies on growth factors, particularly brain-derived neurotrophic factor, glutamate signaling, apoptosis, and inflammation. These data suggest that targeted neuro- protective mechanisms together with an understanding of genetic determinants of susceptibility will usher in a new realm of effective and individualized prevention and treatment of depression. Although the basis of heredity is found in the structure of DNA, the basis of much of the behavioral variance in psy- chiatric disorders is found in gene expression. In the first Translational research article, Renthal and Nestler (p 257) provide a lucid and yet sophisticated discussion of epigen- esis, a remarkable process by which environmental events can be transduced into potentially long-lasting changes in chromatin structure (“chromatin remodeling”) with asso- ciated changes in gene transcription. Not only do epige- netic changes represent a form of cellular memory, but as well they represent compelling explanations for both the development  of  drug  addiction  and  the  behavioral response to stress and to antidepressant treatments. For some psychiatric disorders, environmental and genetic risks alter brain development, resulting in enduring molecular and cellular disturbances in neural circuits, with resultant emergent and characteristic symptomatology. In the sec- ond Translational research article, David Lewis (p 269) performs an anatomical and biochemical dissection of the circuitry of a brain region that mediates cognitive process- es known to be disturbed in schizophrenia, the dorsolater- al prefrontal cortex (DLPFC). In a technically detailed and yet lucid presentation, he describes how developmentally determined deficiencies in γ-aminobutyric acid (GABA) sig- naling and neuronal synchronization in the DLPFC may result in core cognitive and behavioral deficits in schizo- phrenia. In the third article in this section, Belanger and Magistretti (p 281) authoritatively trounce the antiquated yet previously prevalent view that glia are largely inert neur- al components, mere structural nursemaids. Quite to the contrary, astrocytes are major homeostatic defenders of neurons, exquisitely sensitive to and dynamic modulators of neuronal activity. Under pathogenic conditions—neu- roinflammation, oxidative stress, excitotoxicity—not only can the neuroprotective functions of astrocytes be over- whelmed, but as well the astrocytes can paradoxically advance the deleterious processes and the onset of disor- ders like Alzheimer’s disease. In the following article, Drs Wise, Suzuki, and Brown (p 297) update our understand- ing of the dramatic yet highly context-dependent neuro- protective and neuroplastic effects of estradiol. Of particu- lar  clinical  relevance  are  the  observations  of  the anti-inflammatory actions of estradiol and the elegant demonstration that the latency following cessation of ovar- ian function critically determines the cellular and anti- inflammatory effects of estrogen replacement—long laten- cy,  absence  of  beneficial  effects.  These  findings  help explain ostensible contradictions in the literature and sup- port the optimism that estradiol and related steroids may yet be “rescued” as neuroprotective therapeutic agents. In general throughout this volume, neuroplastic and neuro- toxic effects cannot be inferred with certainty absent knowledge of timing and context. In the fifth Transla- tional research article, Drs Gouzoulis-Mayfrank and Dau- mann (p 305) turn our attention from neuroprotection to neurotoxicity in their description of the effects of drugs of abuse, namely MDMA (ecstasy) and the stimulant amphet- amines. Brain morphological and neurochemical abnor- malities (particularly involving serotonergic and dopamin- ergic systems) in animals and brain imaging abnormalities in humans consequent to stimulant abuse are compre- hensively reviewed and juxtaposed with reports of behav- ioral abnormalities. While evidence of the neurotoxicity of these agents is substantial, the authors highlight the lack of parallelism in reported effects and consequent gaps in our knowledge that must critically be addressed.