The projection-specific signals that establish functionally segregated dopaminergic synapses.

Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-ß family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-ß2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-ß and/or Smads.

What is schizophrenia? 25 years of research into schizophrenia - the Age Beginning Course Study.

We studied a population-based sample of 232 first-onset cases of schizophrenia aged 12 to 59 years at first admission retrospectively back to illness onset and prospectively up to 11.2 years later. We compared them with psychiatrically healthy age- and sex-matched population controls and equally matched first-admission patients diagnosed with major depression. At schizophrenia onset women are several years older than men. The social factors tested did not explain the finding. Women's higher level of social development at onset is associated with a better medium-term functional and social outcome. Prodromal schizophrenia and depression are equal in length and diagnostically distinguishable only after the onset of positive symptoms. The sex difference in age at onset, invariable across cultures and ethnicities, is explained by a protective effect of oestrogen, which down-regulates D2 receptors. A higher genetic load antagonizes this effect. Long-term symptom-related illness course exhibits a plateau after three years, the positive symptom dimension after two years, the depressive and the negative dimensions do so after three to five years. The most prevalent symptom is depressive mood. Male first episodes are more frequent and more severe in the first half of life, female ones in the second half. Aetiological conclusions will be drawn.