Alternatively spliced brain-derived neurotrophic factor (BDNF) transcripts are targeted to distinct cellular compartments in neurons but the mechanisms underlying this sorting are unknown. Although only some BDNF isoforms are targeted to dendrites, we have found that the coding region common to all BDNF transcripts contains a constitutively active dendritic targeting signal and that this signal is suppressed in transcripts containing exons 1 or 4, which are restricted to the cell soma and proximal dendrites. This dendritic targeting signal is mediated by translin, an RNA-binding protein implicated in RNA trafficking, and is disrupted by the G196A mutation associated with memory deficits and psychiatric disorders. Molecular modeling and mutational studies indicate that the G196A mutation blocks dendritic targeting of BDNF mRNA by disrupting its interaction with translin. These findings implicate abnormal dendritic trafficking of BDNF mRNA in the pathophysiology of neuropsychiatric disorders linked to the G196A mutation.neuropsychiatric disorders ͉ neurotrophins S everal lines of evidence indicate that targeting of BDNF mRNA to dendrites plays a key role in mediating synaptic plasticity (1-4). However, the molecular mechanisms regulating this process and the differential subcellular localization of alternatively spliced BDNF transcripts, remain to be clarified.Multiple BDNF transcripts are generated by alternative splicing of one 5Ј exon with a shared 3Ј exon containing the entire BDNF coding region and either a short or long 3Ј UTR sequence (5, 6). In recent studies, we have demonstrated that BDNF transcripts differ in their subcellular localization (7). Exon 1 and 4 transcripts are localized in the cell soma, while exon 2 and 6 transcripts show a somato-dendritic localization. Thus, splice variants appear to encode spatial localization signals used to preferentially regulate BDNF expression in different subcellular domains (2, 3). A recent study has suggested that the long 3Ј UTR contains signals necessary for dendritic targeting of BDNF transcripts (4). However, it is unlikely that this mechanism can fully account for the differential dendritic targeting displayed by BDNF transcripts because more than one-third of exon 4 transcripts, which are retained in the soma, contain the long 3Ј UTR. Conversely, more than one-half of exon 6 transcripts, an isoform that displays targeting to dendrites, contain the short 3Ј UTR. To help define the mechanisms underlying differential localization of BDNF transcripts, we have tested the hypothesis that additional signals might be encoded by other BDNF mRNA regions.