Protocadherins and hypothalamic development: do they play an unappreciated role?

Normal brain development requires coordinated cell movements at precise times. It has long been established that cell-cell adhesion proteins of the cadherin superfamily are involved in the adhesion and sorting of cells during tissue morphogenesis. In the present review, we focus on protocadherins, which form the largest subfamily of the cadherin superfamily and mediate homophilic cell-cell adhesion in the developing brain. These molecules are highly expressed during neural development and the exact roles that they play are still emerging. Although, historically, protocadherins were considered to provide mechanical and chemical connections between adjacent cells, recent research suggests that they may also serve as molecular identity markers of neurones to help guide cell recognition and sorting, cell migration, outgrowth of neuronal processes, and synapse formation. This phenomenon of single cell diversity stems, in part, from the vast variation in protein structure, genomic organisation and molecular function of the protocadherins. Although expression profiles and genetic manipulations have provided evidence for the role of protocadherins in the developing brain, we have only begun to construct a complete understanding of protocadherin function. We examine our current understanding of how protocadherins influence brain development and discuss the possible roles for this large superfamily within the hypothalamus. We conclude that further research into these underappreciated but vitally important genes will shed insight into hypothalamic development and perhaps the underlying aetiology of neuroendocrine disorders.

Neurodevelopmental consequences of maternal distress: what do we really know?

A simple internet search of 'maternal stress and pregnancy' turns up hundreds of hits explaining that an adverse intrauterine environment can affect fetal development and potentially lead to various learning, behavioral, and mood disorders in childhood, as well as complex diseases such as obesity and cardiovascular conditions later in life. Indeed, a growing body of literature now links several intrauterine challenges, including maternal obesity and stress, with adverse developmental outcomes in the child. Over the past 5 years, nearly 5000 publications have explored the consequences of maternal distress on young offspring, a marked increase from the 475 published studies over a comparable period 20 years ago. Yet, despite this explosion of research and widespread warnings to pregnant mothers, we still lack a basic understanding of the pathophysiology linking adverse maternal health to the onset of disease in the child, especially regarding how prenatal and perinatal challenges might affect brain development. Recent studies have begun to explore the cellular basis of the abnormal brain cytoarchitecture associated with fetal exposure to intrauterine challenges. Here, our goal is to review the scientific evidence that maternal distress interferes with key neurodevelopmental steps, as an entry point toward mapping the pathophysiology of pre- and perinatal stress on the unborn child's brain.

Synthesis and pharmacological evaluation of ring-methylated derivatives of 3,4-(methylenedioxy)amphetamine (MDA).

The three isomeric ring-methylated derivatives of the well-known hallucinogen and entactogen MDA (1a) were synthesized and evaluated for pharmacological activity as monoamine-releasing agents and as serotonin agonists. The 2-methyl derivative 2a and the 5-methyl derivative 2b were found to be more potent and more selective than the parent compound in inhibiting [3H]-serotonin accumulation in rat brain synaptosomal preparations. Their activity in vivo was confirmed in rats trained to discriminate serotonin-releasing agents and hallucinogens from saline. The results indicate that compounds 2a,b are among the most potent 5-HT-releasing compounds known and show promise as lead compounds in the search for antidepressant drugs that release serotonin rather than inhibit its uptake.