Untitled

104 CHARACTERISTICS OF BRAIN AND BEHAVIORquently, if altered mRNA and protein expression in adult schizophrenic patientsreflects altered neurodevelopmental processes occurring prior to the clinical manifestationof the disease, for instance in childhood or adolescence, these studieswill provide important clues into the development and progression of the diseaseand, more important, identify possible targets for early intervention. This briefreview covers the basic mechanisms of transcriptional regulation, current knowledgeof altered gene expression in schizophrenia focusing on glutamatergic andsynaptic mechanisms, relevance of these gene expression changes to neurodevelopmentand other potential mechanisms of regulation in schizophrenia, andideas about intervention to readjust dysregulated expression.Overview of Transcriptional RegulationTo understand the contribution of gene expression in the manifestation of psychiatricdisorders, a brief overview of transcriptional regulation in eukaryotes is necessary.The central dogma of molecular biology is that cells transcribe DNA intomRNA, and then translate mRNA into protein. That process, although conceptuallysimple, is biochemically complex and subject to regulation at several points.Within the nucleus, DNA exists in a compacted structure, termed chromatin, whichis maintained through interactions with DNA binding proteins, called histones.The structure of the DNA-histone complex, as well as biochemical modificationof the DNA itself (e.g., CpG methylation), affects the accessibility of chromatinto enzymes such as RNA polymerases and other proteins that regulate the transcriptionalprocess (figure 5-1). A second point of regulation is the initiation oftranscription, in which specific sequences within the DNA enhance and promotetranscription. These sequences, known as enhancer sequences and promoter elements,interact with proteins called transcription factors to regulate the degree towhich specific genes are transcribed. Other regulatory elements are sequences inthe DNA that bind transcription factors (also called trans-acting elements) andincrease the activity of RNA polymerase. These regulating elements are usuallylocated upstream of the initiation site but might be found within the gene sequence.The interaction of regulatory elements with different combinations of transcriptionfactors provides a means to differentially regulate transcripts based on stimulusspecificity as well as cell specificity. Many second messenger systems, such asthe cAMP pathway, ultimately regulate gene transcription by altering the levelsor regulatory states of transcription factors (e.g., CREB).In addition, activator and inhibitor proteins also contribute to the process toregulate the strength of transcription. After the DNA is transcribed, RNA processingand modification occur as a third level of regulation. Messenger RNA (mRNA)must be capped at the 5´ end (which protects the RNA from enzymes that degradethe RNA from the 5´ end) and polyadenylated at the 3´ end (for export to the