Differential vulnerability of hippocampal CA3-CA1 synapses to Aβ.

Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer's disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood.

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in 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 Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human can restore Aβ-mediated inhibition on a mouse background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition of LTP.

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.

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.

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.

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.

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.

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

Amyloid β (Aβ) 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 Aβ-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.