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Memory for inconsequential events fades, unless these happen before or after other novel or surprising events. However, our understanding of the neurobiological mechanisms of novelty-enhanced memory persistence is mainly restricted to aversive or fear-associated memories. We now outline an 'everyday appetitive' behavioral model to examine whether and how unrelated novelty facilitates the persistence of spatial memory coupled to parallel electrophysiological studies of the persistence of long-term potentiation (LTP). Across successive days, rats were given one trial per day to find food in different places and later had to recall that day's location. This task is both hippocampus and NMDA receptor dependent. First, encoding with low reward induced place memory that decayed over 24 h; in parallel, weak tetanization of CA1 synapses in brain slices induced early-LTP fading to baseline. Second, novelty exploration scheduled 30 min after this weak encoding resulted in persistent place memory; similarly, strong tetanization--analogous to novelty --both induced late-LTP and rescued early- into late-LTP on an independent but convergent pathway. Third, hippocampal dopamine D1/D5 receptor blockade or protein synthesis inhibition within 15 min of exploration prevented persistent place memory and blocked late-LTP. Fourth, symmetrically, when spatial memory was encoded using strong reward, this memory persisted for 24 h unless encoding occurred under hippocampal D1/D5 receptor blockade. Novelty exploration before this encoding rescued the drug-induced memory impairment. Parallel effects were observed in LTP. These findings can be explained by the synaptic tagging and capture hypothesis. hippocampus | flashbulb memory | synaptic plasticity | dopamine | protein synthesis doi/ 10.1073/pnas.1008638107

Whether estrogen replacement is beneficial to cognitive health is controversial. Some studies have shown that estrogen replacement therapy (ERT) relieves memory impairment associated with menopause in women, whereas others suggest that estrogen not only is incapable of providing a benefit, but actually can be detrimental. One possible explanation for this discrepancy in study findings could be the varying time after menopause at which ERT is initiated. It has been proposed that a critical period exists during which ERT must be administered to enhance cognitive function. This idea has yet to be tested directly using functional synaptic studies, however. Here we investigated whether prolonged hormone deprivation caused by ovariectomy (OVX) in young adult rats prevents the ability of estrogen replacement to increase synaptic function in the hippocampus to a degree necessary for estrogen-induced improvement in learning and memory. Remarkably, estrogen replacement was found to increase long-term potentiation, the current mediated by NR2B-containing NMDA receptors, and the dendritic spine density at CA3-CA1 synapses up to 15 months post-OVX. However, by 19 months post-OVX, the same estrogen replacement was unable to induce these changes. Importantly, this loss of estrogen's effectiveness was seen to be a consequence of the duration of deprivation. In female rats aged with their ovaries intact and examined at the same chronological age as the 19-month post-OVX group, estrogen replacement significantly increased synaptic function and spine density. These data clearly demonstrate that a critical period exists during which ERT must be administered, and that once this period passes, the beneficial effects are lost. aging | estradiol | long-term potentiation | NR2B | spines doi/ 10.1073/pnas.1009307107

Synaptic rules that may determine the interaction between coexisting forms of long-term potentiation (LTP) at glutamatergic central synapses remain unknown. Here, we show that two mechanistically distinct forms of LTP could be induced in thalamic input to the lateral nucleus of the amygdala (LA) with an identical presynaptic stimulation protocol, depending on the level of postsynaptic membrane polarization. One form of LTP, resulting from pairing of postsynaptic depolarization and low-frequency presynaptic stimulation, was both induced and expressed postsynaptically ('post-LTP'). The same stimulation in the absence of postsynaptic depolarization led to LTP, which was induced and expressed presynaptically ('pre-LTP'). The inducibility of coexisting pre--and postsynaptic forms of LTP at synapses in thalamic input followed a well-defined hierarchical order, such that pre-LTP was suppressed when post-LTP was induced. This interaction was mediated by activation of cannabinoid type 1 receptors by endogenous cannabinoids released in the lateral nucleus of the amygdala in response to activation of the type 1 metabotropic glutamate receptor. These results suggest a previously unknown mechanism by which the hierarchy of coexisting forms of long-term synaptic plasticity in the neural circuits of learned fear could be established, possibly reflecting the hierarchy of memories for the previously experienced fearful events according to their aversiveness level. synaptic transmission | glutamate | plasticity | endocannabinoids doi/ 10.1073/pnas.1009803107

Experience-dependent cortical plasticity has been studied by using loss-of-function methods. Here, we take the complementary approach of using a genetic gain-of-function that enhances plasticity. We show that a constitutively active form of H-ras ([H-ras.sup.G12V]), expressed presynaptically at excitatory synapses in mice, accelerates and enhances multiple, mechanistically distinct forms of plasticity in the developing visual cortex. In vivo, [H-ras.sup.G12V] not only increased the rate of ocular dominance change in response to monocular deprivation (MD), but also accelerated recovery from deprivation by reverse occlusion. In vitro, [H-ras.sup.G12v] expression decreased baseline presynaptic release probability and enhanced presynaptically expressed longterm potentiation (LTP). [H-ras.sup.G12v] expression also accelerated the increase following M D in the frequency of miniature excitatory potentials, mirroring accelerated plasticity in vivo. These findings demonstrate accelerated neocortical plasticity, which offers an avenue toward future therapies for many neurological and neuropsychiatric disorders. gain of function | monocular deprivation | mouse | ocular dominance | presynaptic long-term potentiation doi/ 10.1073/pnas.1013866107

How persistent synaptic and spine modification is achieved is essential to our understanding of developmental refinement of neural circuitry and formation of memory. Within a short period after their induction, both types of modifications can eitherC be stabilized or reversed, but how this reversibility is controlled is largely unknown. We have shown previously that AMPA receptors (AMPARs) are delivered to perisynaptic regions after the induction of long-term potentiation (LTP) but are absent from perisynaptic regions after the full expression of LTP. Here, we report that perisynaptic AMPARs are GluR2-lacking and they translocate to synapses in a protein kinase C (PKC)-dependent manner. Once entering synapses, these AMPARs quickly switch to GluR2-containing in an activity-dependent manner. Absence of postinduction activity or blocking interactions between GluR2 and NSF, or GluR2 and GRIP/ PICK1 results in LTP mediated by GluR2-1acking AMPARs. However, these synaptic GluR2-1acking AMPARs are not sufficient to allow reversibility of LTP. On the other hand, postsynaptic inhibition of PKC activity hords AMPARs at perisynaptic regions. As long as perisynaptic AMPARs are present, both LTP and spine expansion remain labile: they can be reverted to the baseline state together with removal of perisynaptic AMPARs, or they can enter a stabilized state of persistent increase together with synaptic incorporation of perisynaptic AMPARs. Thus, perisynaptic GluR2-1acking AMPARs play a critical role in controlling the reversibility of both synaptic and spine modifications, dendritic spine | long-term potentiation | two-photon imaging doi/ 10.1073/pnas.0913004107

Proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) domains play key roles in the assembly and regulation of cellular signaling pathways and represent putative targets for new pharmacotherapeutics. Here we describe the first small-molecule inhibitor (FSC231) of the PDZ domain in protein interacting with C kinase 1 (PICK1) identified by a screening of ~44,000 compounds in a fluorescent polarization assay. The inhibitor bound the PICK1 PDZ domain with an affinity similar to that observed for endogenous peptide ligands ([K.sub.i]~10.1 [micro]M). Mutational analysis, together with computational docking of the compound in simulations starting from the PDZ domain structure, identified the binding mode of FSC231. The specificity of FSC231 for the PICK1 PDZ domain was supported by the lack of binding to PDZ domains of postsynaptic density protein 95 (PSD-95) and glutamate receptor interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal neurons after internalization in response to NMDA receptor activation. FSC231 blocked the expression of both long-term depression and long-term potentiation in hippocampal CA1 neurons from acute slices, consistent with inhibition of the bidirectional function of PICK1 in synaptic plasticity. Given the proposed role of the PICK1/AMPA receptor interaction in neuropathic pain, excitotoxicity, and cocaine addiction, FSC231 might serve as a lead in the future development of new therapeutics against these conditions. drug discovery | fluorescence polarization | protein-protein interactions | synaptic plasticity | AMPA receptors www.pnas.org/cgi/doi/10.1073/pnas.0902225107

Zif268 is a transcriptional regulator that plays a crucial role in maintenance of the late phases of hippocampal long-term potentiation (LTP) and consolidation of spatial memories. Because the hippocampal place cell system is essential for long-term spatial memory, we tested the hypothesis that zif268 is required for long-term stability of hippocampal place cell representations by recording CA1 place cells in mice lacking zif268. We found that zif268 gene deletion destabilized the representation of a familiar environment after exposure to a novel environment and impaired the long-term (24 h), but not short-term (1 h), stability of newly formed representations. These impairments could be rescued by repeated exposure to the novel environment, however. These results indicate that zif268 contributes to the long-term stability of spatial representations in CA1 and support the notion that the long-term stability of place cell representations requires transcription-dependent mechanisms similar to those observed in LTP. hippocampus | spatial memory

Excitatory synapses in the brain undergo activity-dependent changes in the strength of synaptic transmission. Such synaptic plasticity as exemplified by long-term potentiation (LTP) is considered a cellular correlate of learning and memory. The presence of G protein-activated inwardly rectifying [K.sup.+] (GIRK) channels near excitatory synapses on dendritic spines suggests their possible involvement in synaptic plasticity. However, whether activity-dependent regulation of GIRK channels affects excitatory synaptic plasticity is unknown. In a companion article we have reported activity-dependent regulation of GIRK channel density in cultured hippocampal neurons that requires activity of NMDA receptors (NMDAR) and protein phosphatase-1 (PP1) and takes place within 15 min. In this study, we performed whole-cell recordings of cultured hippocampal neurons and found that NMDAR activation increases basal GIRK current and GIRK channel activation mediated by adenosine [A.sub.1] receptors, but not GABAB receptors. Given the similar involvement of NMDARs, adenosine [A.sub.1] receptors, and PP1 in depotentiation of LTP caused by low-frequency stimulation that immediately follows LTP-inducing high-frequency stimulation, we wondered whether NMDAR-induced increase in GIRK channel surface density and current may contribute to the molecular mechanisms underlying this specific depotentiation. Remarkably, GIRK2 null mutation or GIRK channel blockade abolishes depotentiation of LTP, demonstrating that GIRK channels are critical for depotentiation, one form of excitatory synaptic plasticity. adenosine receptor | synaptic plasticity learning and memory | protein phosphatase-1 | extracellular field recording

Neuroligin-1 is a potent trigger for the de novo formation of synaptic connections, and it has recently been suggested that it is required for the maturation of functionally competent excitatory synapses. Despite evidence for the role of neuroligin-1 in specifying excitatory synapses, the underlying molecular mechanisms and physiological consequences that neuroligin-1 may have at mature synapses of normal adult animals remain unknown. By silencing endogenous neuroligin-1 acutely in the amygdala of live behaving animals, we have found that neuroligin-1 is required for the storage of associative fear memory. Subsequent cellular physiological studies showed that suppression of neuroligin-1 reduces NMDA receptor-mediated currents and prevents the expression of long-term potentiation without affecting basal synaptic connectivity at the thalamo-amygdala pathway. These results indicate that persistent expression of neuroligin-1 is required for the maintenance of NMDAR-mediated synaptic transmission, which enables normal development of synaptic plasticity and long-term memory in the amygdala of adult animals. synaptic plasticity | neuroligin | autism