Showing papers by "Ole Paulsen published in 2011"

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

Abstract: 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. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.

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

Abstract: 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.

Presynaptic induction and expression of timing-dependent long-term depression demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist

Abstract: NMDA receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). To help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. We used this method to investigate timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use-dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses.

Hippocampal mossy fiber long‐term depression in Grm2/3 double knockout mice

Abstract: Group II metabotropic glutamate receptors (mGluR2, encoded by Grm2, and mGluR3, encoded by Grm3) are inhibitory autoreceptors that negatively modulate the adenylate cyclase signaling cascade. Within the hippocampus, mGluR2 is believed to play a key role in the induction of long-term depression (LTD) at mossy fiber-CA3 synapses. Here, we used Grm2/3 double knockout (dko) mice to investigate to what extent group II mGluRs are necessary for mossy fiber LTD. Surprisingly, we found that these mice displayed prominent mossy fiber LTD. However, the induction of this form of LTD was sensitive to the external Ca(2+) concentration. Mossy fiber LTD in Grm2/3 dko mice was indistinguishable from that in wild-type mice at 4 mM Ca(2+) , but largely absent at 2 mM external Ca(2+) . Mossy fiber LTD in Grm2/3 dko mice was not blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D-AP5, confirming that the observed response did not reflect NMDA receptor-dependent LTD in contaminating associational-commissural fibers, and enabling us to use the NMDA receptor-mediated EPSC to monitor mossy fiber LTD. Using whole-cell recordings, we demonstrated that LTD of the NMDA receptor-mediated EPSC in Grm2/3 dko mice was not affected by intracellular application of BAPTA and CsF to block postsynaptic Ca(2+) and G-protein-mediated effects. This presynaptic LTD was, however, blocked by the AMPA/kainate receptor antagonist, NBQX. Thus, an activity-dependent, external Ca(2+) concentration-sensitive form of mossy fiber LTD can be induced in Grm2/3 dko mice. Two mGluR antagonists also failed to block mossy fiber LTD under 4 mM conditions in wild-type mice, strengthening the conclusion that group II mGluRs are not obligatory for mossy fiber LTD.

Phase of firing as a local window for efficient neuronal computation: tonic and phasic mechanisms in the control of theta spike phase.

Abstract: The nature of the neural code remains a central issue of contention in neuroscience. Firing rate based schemes have dominated thinking for most of the past century, but there is a growing acceptance that temporal patterns of neuronal activity have an important role to play, at least in some systems and circumstances. Neuronal oscillations provide a central pillar in the evidence supporting temporal coding, perhaps because temporal codes can ultimately be understood only in the context of population activity and oscillations are at once experimentally accessible and analytically tractable. In the many roles proposed for oscillatory activity, a uniting theme is the control of spike timing, which can broadly be considered on two timescales. On the one hand, fast oscillations may be important in promoting precise synchronization of activity across cells, by providing millisecond windows of enhanced spike probability. Slow oscillations, on the other hand, can provide a broader temporal scaffold, against which other inputs, both tonic and phasic, can determine spike timing on the order of milliseconds to tens of milliseconds. Again, this could be important for synchronization of activity, but equally, could be used to control spike order, for coding, or plasticity purposes, or could be used to desynchronize discrete assemblies, enabling parallel processing. Here, we describe the cellular mechanisms underlying this broader timescale process in the hippocampus, specifically focusing on the effect of tonic and phasic inputs on the control of spike timing in single hippocampal neurons during theta oscillations and the implications for information coding and storage.

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

Abstract: Corrigendum: Hemisphere-specific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity