Rethinking CNS disorders: Time for new drug targets?

摘要

Human psychiatric disorders are complex, widespread, and their etiology remains poorly understood [1,2]. Traditionally, brain disorders are studied by establishing unique genetic and molecular determinants for major syndromes and specific affected phenotypes [3,4]. For example, complex central nervous system (CNS) symptoms are often deconstructed into endophenotypes -the smaller 'units' in the gene-to-behavior pathway [5,6]. Introduced by Gottes-man in the 1970s, endophenotypes represent measurable heritable physiological, behavioral, or anatomical bio-markers for phenotypic traits [6,7]. Endophenotypes are related to a disorder in the general population (general population unaffected relatives < patients) and share common genetic influences with the disease [8]. Thus, identifying disordered endophenotypes and exploring their genetic and molecular mechanisms can lead to important CNS drug targets and efficient therapies. Endophenotypes can often be grouped into domains - their larger clusters (Figure 1) - such as anxiety/depression-related behaviors (affective domain), aberrant memory/ learning (cognitive domain), social deficits (social domain), and altered activity parameters (motor domain) [4,11].