The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.

These findings establish minocycline as a promising therapeutic for the treatment of fragile X mental retardation.

Matrix metalloproteinases (MMPs) play critical roles in egg fertilization, embryonic development, wound repair, cancer, and inflammatory and neurologic diseases. This subfamily of metzincin peptidases can cleave extracellular matrix (ECM) and pericellular proteins that have profound effects on cell behavior. Among known MMP substrates are several proteins that play important roles in synaptogenesis, synaptic plasticity, and long-term potentiation (LTP). In this Mini-Review we discuss how MMP-directed cleavage of these proteins can impact the formation and function of synapses within the brain. Pyramidal neurons in the hippocampus, and other large neurons, are surrounded by perineuronal nets that are composed of brevican, tenascin-R, and laminin, each of which is subject to proteolytic cleavage by MMPs. Tenascin-R knockout mice show deficits in learning and memory and LTP, as do at least two MMP knockouts. Impaired LTP is also seen in brain-derived neurotrophic factor (BDNF) knockout mice, which is interesting in that pro-BDNF can be processed into mature BDNF by several MMPs and thereby regulate activation of the high-affinity BDNF receptor TrkB. At the synaptic level, MMP substrates also include ephrins, Eph receptors, and cadherins, which are also involved in synapse development and plasticity. MMPs can also process membrane-bound tumor necrosis factor-alpha into a potent soluble cytokine that is increasingly implicated in neuron-glial signaling, particularly in neurologic disease. Finally, we discuss how the development of therapeutics to attenuate MMP activity in neurodegenerative disorders may become powerful tools for future studies of synaptic formation and function within the developing and mature brain.

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Here, using a genetic approach, we dissect the roles of EphB receptor tyrosine kinases in dendritic spine development. Analysis of EphB1, EphB2, and EphB3 double and triple mutant mice lacking these receptors in different combinations indicates that all three, although to varying degrees, are involved in dendritic spine morphogenesis and synapse formation in the hippocampus. Hippocampal neurons lacking EphB expression fail to form dendritic spines in vitro and they develop abnormal spines in vivo. Defective spine formation in the mutants is associated with a drastic reduction in excitatory glutamatergic synapses and the clustering of NMDA and AMPA receptors. We show further that a kinase-defective, truncating mutation in EphB2 also results in abnormal spine development and that ephrin-B2–mediated activation of the EphB receptors accelerates dendritic spine development. These results indicate EphB receptor cell autonomous forward signaling is responsible for dendritic spine formation and synaptic maturation in hippocampal neurons.