Two forms of long-term depression in a polysynaptic pathway in the leech CNS: one NMDA receptor-dependent and the other cannabinoid-dependent

Although long-term depression (LTD) is a well-studied form of synaptic plasticity, it is clear that multiple cellular mechanisms are involved in its induction. In the leech, LTD is observed in a polysynaptic connection between touch mechanosensory neurons (T cells) and the S interneuron following low frequency stimulation. LTD elicited by 450 s low frequency stimulation was blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonists. However, LTD elicited by 900 s low frequency stimulation was insensitive to NMDA receptor antagonists and was instead dependent on cannabinoid signaling. This LTD was blocked by both a cannabinoid receptor antagonist and by inhibition of diacylglycerol lipase, which is necessary for the synthesis of the cannabinoid transmitter 2-arachidonyl glycerol (2-AG). Bath application of 2-AG or the cannabinoid receptor agonist CP55 940 also induced LTD at this synapse. These results indicate that two forms of LTD coexist at the leech T-to-S polysynaptic pathway: one that is NMDA receptor-dependent and another that is cannabinoid-dependent and that activation of either form of LTD is dependent on the level of activity in this circuit. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Rac signaling in breast cancer: a tale of GEFs and GAPs

Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy.     

Lipid changes in the aged brain: effect on synaptic function and neuronal survival

As the brain ages, cognitive and motor performance decline. This decline is thought to be largely due to the accumulation of damaging products from normal oxidative metabolism and to the perturbation of general body homeostasis and brain-circulation separation. Despite this abundance of insults, the aged brain contains few dead neurons, suggesting that aging must be paralleled by triggering or enhancing neuronal survival mechanisms. Recent evidence points to the contribution of changes in the lipid composition of membranes to both age-dependent cognitive decline and robust neuronal survival. In this review, we describe and discuss the current understanding of the roles of lipids in neuronal aging, with special attention to their influence on membrane fusion, neurotransmitter receptor dynamics and survival/death signaling pathways.     

Computation,wiring, and plasticity in synaptic clusters

Synaptic clusters on dendrites are extraordinarily compact computational building blocks. They contribute to key local computations through biophysical and biochemical signaling that utilizes convergence in space and time as an organizing principle. However, these computations can only arise in very special contexts. Dendritic cluster computations, their highly organized input connectivity, and the mechanisms for their formation are closely linked, yet these have not been analyzed as parts of a single process. Here, we examine these linkages. The sheer density of axonal and dendritic arborizations means that there are far more potential connections (close enough for a spine to reach an axon) than actual ones. We see how dendritic clusters draw upon electrical, chemical, and mechano–chemical signaling to implement the rules for formation of connections and subsequent computations. Crucially, the same mechanisms that underlie their functions also underlie their formation.