A␤ 1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid ␤ protein (A␤) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible A␤ oligomers (referred to as ADDLs, for A␤-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of A␤-derived diffusible ligands acting upon particular neural signal transduction pathways.

Since Costello’s (1972) seminal Behavior Therapy article on loss of reinforcers or reinforcer effectiveness in depression, the role of reward sensitivity and processing in both depression and bipolar disorder has become a central area of investigation. In this article, we review the evidence for a model of reward sensitivity in mood disorders, with unipolar depression characterized by reward hyposensitivity and bipolar disorders by reward hypersensitivity. We address whether aberrant reward sensitivity and processing are correlates of, mood-independent traits of, vulnerabilities for, and/or predictors of the course of depression and bipolar spectrum disorders, covering evidence from self-report, behavioral, neurophysiological, and neural levels of analysis. We conclude that substantial evidence documents that blunted reward sensitivity and processing are involved in unipolar depression and heightened reward sensitivity and processing are characteristic of hypomania/mania. We further conclude that aberrant reward sensitivity has a trait component, but more research is needed to clearly demonstrate that reward hyposensitivity and hypersensitivity are vulnerabilities for depression and bipolar disorder, respectively. Moreover, additional research is needed to determine whether bipolar depression is similar to unipolar depression and characterized by reward hyposensitivity, or whether like bipolar hypomania/mania, it involves reward hypersensitivity.

Across development, maternal depression has been found to be a risk factor for youth psychopathology generally and youth depression specifically. Maternal Expressed Emotion (EE) has been examined as a predictor of outcome among youth with depression. The present study explored the associations between youth psychopathology and two predictors-maternal depression within the child's lifetime and maternal EE-in a study of children at risk for depression. One hundred and seventy-one youth, ages 8-12, and their mothers participated. To assess maternal and youth psychopathology, dyads were administered structured diagnostic assessments, and mothers and children completed self-report measures of their own depressive symptoms. In addition, mothers completed the Achenbach Child Behavior Checklist-Parent Report Version (CBCL) for their children. Maternal EE was assessed based on the Five Minute Speech Sample. History of maternal depression was associated with high maternal EE, and the combination of maternal depression history and maternal EE was associated with children's own reports of higher depressive symptoms. Current maternal depressive symptoms were associated with mothers' reports of children's Internalizing scores on the CBCL, and maternal depression history, current maternal depressive symptoms, and maternal EE were strongly associated with mothers' reports of children's Externalizing and Total Problem scores on the CBCL. History of maternal depression and a rating of high or borderline Critical EE (characterized by maternal critical comments and/or reports of a negative relationship) were independently associated with children's depression diagnoses.

Insight into the mechanisms of synaptic modulation is important for understanding information processing in the central nervous system (CNS). Modulation of synaptic transmission occurs at several sites: at presynaptic terminals, by the activation of presynaptic receptors; at postsynaptic cells, by change in the postsynaptic receptor properties; and at the synaptic cleft, by change in the clearance rate of released transmitter. At the presynaptic terminal there exist at least four identifiable targets for modulation of release by receptors. (1) Changes in presynaptic resting Ca 2+ concentrations, either by the opening or closing of presynaptic ligand-gated Ca