Hippocampal Neurogenesis Reduces the Dimensionality of Sparsely Coded Representations to Enhance Memory Encoding.

Adult neurogenesis in the hippocampal dentate gyrus (DG) of mammals is known to contribute to memory encoding in many tasks. The DG also exhibits exceptionally sparse activity compared to other systems, however, whether sparseness and neurogenesis interact during memory encoding remains elusive. We implement a novel learning rule consistent with experimental findings of competition among adult-born neurons in a supervised multilayer feedforward network trained to discriminate between contexts. From this rule, the DG population partitions into neuronal ensembles each of which is biased to represent one of the contexts. This corresponds to a low dimensional representation of the contexts, whereby the fastest dimensionality reduction is achieved in sparse models. We then modify the rule, showing that equivalent representations and performance are achieved when neurons compete for synaptic stability rather than neuronal survival. Our results suggest that competition for stability in sparse models is well-suited to developing ensembles of what may be called memory engram cells.

12-Lipoxygenase regulates hippocampal long-term potentiation by modulating L-type Ca2+ channels.

Although long-term potentiation (LTP) has been intensively studied, there is disagreement as to which molecules mediate and modulate LTP. This is partly attributable to the presence of mechanistically distinct forms of LTP that are induced by different patterns of stimulation and that depend on distinct Ca(2+) sources. Here, we report a novel role for the arachidonic acid-metabolizing enzyme 12-lipoxygenase (12-LO) in LTP at CA3-CA1 hippocampal synapses that is dependent on the pattern of tetanic stimulation. We find that 12-LO activity is required for the induction of LTP in response to a theta burst stimulation protocol that depends on Ca(2+) influx through both NMDA receptors and L-type voltage-gated Ca(2+) channels. In contrast, LTP induced by 100 Hz tetanic stimulation, which requires Ca(2+) influx through NMDA receptors but not L-type channels, does not require 12-LO. We find that 12-LO regulates LTP by enhancing postsynaptic somatodendritic Ca(2+) influx through L-type channels during theta burst stimulation, an action exerted via 12(S)-HPETE [12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid], a downstream metabolite of 12-LO. These results help define the role of a long-disputed signaling enzyme in LTP.

Calcium release from presynaptic ryanodine-sensitive stores is required for long-term depression at hippocampal CA3-CA3 pyramidal neuron synapses.

Although Ca2+ release from internal stores has been proposed to be important for the induction of long-term synaptic plasticity, the importance of Ca2+ stores localized in presynaptic terminals remains unclear. Here, we have selectively applied pharmacological antagonists to either the presynaptic or postsynaptic cell in paired whole-cell recordings from hippocampal CA3 pyramidal neurons in slice culture. We demonstrate directly the necessary role of presynaptic, but not postsynaptic, ryanodine-sensitive Ca2+ stores in the induction of NMDA receptor (NMDAR)-dependent long-term depression (LTD). Using two-photon laser scanning microscopy, we further find that release from the ryanodine-sensitive stores during prolonged synaptic stimulation generates a slowly rising Ca2+ signal in the presynaptic terminal that is required for the induction of LTD. Moreover, this form of LTD has a significant presynaptic component of expression because it causes a marked decrease in the rate of release from CA3 neuron presynaptic terminals of FM 1-43, a fluorescent probe of synaptic vesicle cycling. Thus, Ca2+ release from presynaptic ryanodine-sensitive stores is critical in the induction of a presynaptic component of NMDAR-dependent LTD.

The Frizzled-1/(beta(2))-adrenergic receptor chimera: pharmacological properties of a unique G protein-linked receptor.

The frizzled gene family of Wnt receptors encodes proteins that have a seven-transmembrane-spanning motif characteristic of G-protein-coupled receptors. Using a chimeric receptor composed of the exofacial and the transmembrane, ligand-binding domain of the beta(2)-adrenergic receptor (beta2AR) fused with the corresponding cytoplasmic domains of the rat Frizzled-1 receptor (Rfz1), we created a unique chimera between distant members of the superfamily of G protein-coupled receptors. Herein, we describe the pharmacological properties of the chimera, which represents a receptor in which the exofacial and cytoplasmic domains are minimized in length. This unique chimera retains much of the pharmacological character of the native beta2AR, whereas the coupling can be ascribed to Rfz1 domains which operate via G alpha q and not G alpha s. The Rfz1 chimera demonstrates a robust agonist (isoproterenol)-induced sequestration. Since the Rfz1 cytoplasmic domains possess canonical sites for several protein kinases, we were able to investigate the effects of kinase inhibitors on Rfz1 chimera sequestration. Only the protein kinase A inhibitor KT5720, but not inhibitors of protein kinase C, calcium/calmodulin-sensitive kinase-2, casein kinase-2, and Src, inhibited agonist-induced sequestration. Expression of a dominant-negative form of beta-arrestin blocked sequestration of the beta2AR, but only reduced modestly that of the Rfz1 chimera. These data demonstrate that the Frizzled-1 chimera displays cardinal features of a G protein-coupled receptor, including agonist-induced sequestration, but appears to do so largely even in the presence of dominant-negative beta-arrestins.