Left-right dissociation of hippocampal memory processes in mice.

Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation.

Amyloid ß (Aß) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aß-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aß-induced impairment of LTP. Moreover, we show that Aß increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aß and prevents Aß-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aß to impair synaptic plasticity in the hippocampus and suggest that the Aß-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aß and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

Differential vulnerability of hippocampal CA3-CA1 synapses to Aß.

Amyloid-beta (Aß) and tau protein are both involved in the pathogenesis of Alzheimer's disease. Aß produces synaptic deficits in wild-type mice that are not seen in Mapt-/- mice, suggesting that tau protein is required for these effects of Aß. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aß are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aß1-42 (hAß) in wild-type (WT) mice, but not in tau-knockout (Mapt-/-) mice. We then tested whether NMDAR currents were affected by hAß; we found that hAß reduced the postsynaptic NMDAR current in WT mice but not in Mapt-/- mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25-6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt-/- mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt-/- mice, thus differential NMDAR subunit expression does not explain the difference in hAß effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hAß in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hAß exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to Aß and that a genetic knock out of tau protein protects them from Aß synaptotoxicity.

Wild-Type, but Not Mutant N296H, Human Tau Restores Aß-Mediated Inhibition of LTP in Tau-/- mice.

Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aß-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore Aß-mediated inhibition on a mouse Tau-/- background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aß-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human MAPT locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a Tau-/- background. We found that the human wild-type MAPT H1 locus was able to restore Aß42-mediated impairment of LTP. In contrast, Aß42 did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human MAPT is able to restore Aß42-mediated inhibition of LTP in Tau-/- mice. These results provide further evidence that tau protein is central to Aß-induced LTP impairment and provide a valuable tool for further analysis of the links between Aß, human tau and impairment of synaptic function.

Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH.

Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals.

Synaptic Plasticity and Memory: New Insights from Hippocampal Left-Right Asymmetries.

All synapses are not the same. They differ in their morphology, molecular constituents, and malleability. A striking left-right asymmetry in the distribution of different types of synapse was recently uncovered at the CA3-CA1 projection in the mouse hippocampus, whereby afferents from the CA3 in the left hemisphere innervate small, highly plastic synapses on the apical dendrites of CA1 pyramidal neurons, whereas those originating from the right CA3 target larger, more stable synapses. Activity-dependent modification of these synapses is thought to participate in circuit formation and remodeling during development, and further plastic changes may support memory encoding in adulthood. Therefore, exploiting the CA3-CA1 asymmetry provides a promising opportunity to investigate the roles that different types of synapse play in these fundamental properties of the CNS. Here we describe the discovery of these segregated synaptic populations in the mouse hippocampus, and discuss what we have already learnt about synaptic plasticity from this asymmetric arrangement. We then propose models for how the asymmetry could be generated during development, and how the adult hippocampus might use these distinct populations of synapses differentially during learning and memory. Finally, we outline the potential implications of this left-right asymmetry for human hippocampal function, as well as dysfunction in memory disorders such as Alzheimer's disease.

GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity.

N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.

Hemisphere-specific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity.

Postsynaptic spines at CA3-CA1 synapses differ in glutamate receptor composition according to the hemispheric origin of CA3 afferents. To study the functional consequences of this asymmetry, we used optogenetic tools to selectively stimulate axons of CA3 pyramidal cells originating in either left or right mouse hippocampus. We found that left CA3 input produced more long-term potentiation at CA1 synapses than right CA3 input as a result of differential expression of GluN2B subunit-containing NMDA receptors.