Amyloid β Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation

Alzheimer’s disease (AD) is associated with an early hippocampal dysfunction, which is likely induced by an increase in soluble amyloid beta peptide (Aβ). This hippocampal failure contributes to the initial memory deficits observed both in patients and in AD animal models and possibly to the deterioration in activities of daily living (ADL). One typical rodent behavior that has been proposed as a hippocampus-dependent assessment model of ADL in mice and rats is burrowing. Despite the fact that AD transgenic mice show some evidence of reduced burrowing, it has not been yet determined whether or not Aβ can affect this typical rodent behavior and whether this alteration correlates with the well-known Aβ-induced memory impairment. Thus, the purpose of this study was to test whether or not Aβ affects burrowing while inducing hippocampus-dependent memory impairment. Surprisingly, our results show that intrahippocampal application of Aβ increases burrowing while inducing memory impairment. We consider that this Aβ-induced increase in burrowing might be associated with a mild anxiety state, which was revealed by increased freezing behavior in the open field, and conclude that Aβ-induced hippocampal dysfunction is reflected in the impairment of ADL and memory, through mechanisms yet to be determined

Intrabulbar Aβ application induces permanent deposits.

<p>A, Photomicrographs of histological sections stained with toluidine-blue taken from both vehicle (left) and Aβ-injected (right) animals showing the lesion induced by the microinjector. Note that the microinjector reaches the granule cell layer. B, Schematic representation (adapted from Paxinos and Watson [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075745#B58" target="_blank">58</a>]) of the microinjector tip locations, represented as a gray circles, in both bulbi of all animals. B denotes the position of Bregma. C, Photomicrograph illustrating thiazine red positive plaques stained in the <i>subiculum</i> of a 19-month-old triple transgenic (3xTgAD) mouse. D, Photomicrographs of histological sections, stained with thiazine red, from both vehicle (left) and Aβ-injected (right) animals. Note that Aβ-treated animals exhibit thiazine red deposits, whereas vehicle-treated animals do not. The t denotes the track left by the microinjector. Scale-bars denote 1 mm for A, and 200 µm for C and for the micrographs in D.</p

Amyloid beta (Aβ) inhibits spontaneous network activity in the olfactory bulb (OB) of mice and rats.

<p>A, Representative recordings of the OB spontaneous network activity in slices, filtered at highpass = 0.5 Hz and lowpass = 1.5 KHz, obtained from 8-week-old mice in control conditions (upper trace), after 60 min of Aβ exposure (middle trace), and after 30 min of washout (lower trace). B, Averaged power spectra (± standard error; shaded area) of the slices under the three experimental conditions shown in A. Note that OB spontaneous network activity includes a broad variety of frequencies and that Aβ application produces a generalized and reversible reduction of the power without preferentially affecting any frequency range. C, Quantification of the power of OB network activity (as % of control) for different frequency bands (theta, beta, and gamma) for the experimental conditions represented in A. Note that Aβ reversibly reduces the power of the OB network activity to the same degree for all frequencies. D, Time-course of Aβ-induced inhibition of OB network activity, as % of control, over a frequency range of 1 to 50 Hz, and its washout. E, Comparison of Aβ-induced inhibition of OB network activity and its washout recorded in slices obtained from mice and rats. Note that the phenomenon is identical in slices obtained from both species. * Denotes a significant difference (p < 0.05) relative to the control (n = 7).</p

Aβ-induced olfactory disruption is not associated with alterations in motivation to seek food or motor performance.

<p>A, Quantification of time needed to reach food for control animals (injected with vehicle; white bars) and animals with intrabulbar injection of Aβ (gray bars) in two conditions: Food-deprived and Fed. Additionally, animals were tested while food was either hidden (a chocolate piece) or in plain sight (normal chow). Note that the animals injected with Aβ exhibit a deficit in their ability to find the hidden food, regardless of their feeding status. In contrast, no difference was found for any experimental group when the food was visible. Note that just for these experiments the data are represented as the median and the interquartile range. B, Time-course of body weight increase, quantified as % of the original weight (on the day of surgery), for animals injected with vehicle and animals with intrabulbar injection of Aβ. C, Food intake of control animals injected with vehicle (white bars) and animals with intrabulbar injection of Aβ (gray bars) tested at two time points (30 min upper graph and 120 min, lower graph). * Denotes a significant difference relative to control (vehicle; p < 0.05).</p

Aβ-induced inhibition of OB network activity is age and concentration dependent.

<p>A, Averaged power spectra (± standard error) of the slices obtained from 3-week-old animals in control conditions (dark gray) and after 1 h of continuous application of 30 nM Aβ (light gray). The inset shows representative recordings, filtered at highpass = 0.5 Hz and lowpass = 1.5 KHz, for both conditions using the same color code. B, Quantification of the power of OB network activity (as % of control) over a frequency range of 1 to 50 Hz after the application of different concentrations of Aβ to slices obtained from 3-week-old animals. Note that Aβ reduces OB network activity only at the highest concentration tested. C and D, Same as A and B except the slices were obtained from 6-week-old animals. Note that Aβ reduces OB network activity at the two highest concentrations tested. D and F, Same as A and B except the slices were obtained from 8-week-old animals. Note that Aβ reduces OB network activity at the two highest concentrations tested and that 3 nM Aβ also tends to reduce the activity. * Denotes a significant difference relative to control, and # denotes a significant difference between conditions (p < 0.05).</p

OB network activity is stable through time and is not affected by the inverse Aβ sequence.

<p>A, Averaged power spectra (± standard error) of the slices in control conditions (dark gray) and after 3 h of continuous recording under the same control conditions (light gray). The insets shows representative recordings, filtered at highpass = 0.5 Hz and lowpass = 1.5 KHz for both conditions using the same color code. B, Quantification of the power of OB network activity (as % of control) over a frequency range of 1 to 50 Hz at three different time points. Note that OB network activity remains unaltered for at least 3 h of recording. C, Averaged power spectra (± standard error) of the slices in control conditions (dark gray) and after 1 h of continuous application of the Aβ inverse sequence (42-1, light gray). The insets show representative recordings for both conditions (using the same color code). D, Quantification of the power of OB network activity (as % of control) over a frequency range of 1 to 50 Hz 1 h after application of the inverse Aβ sequence, showing no effect of the peptide.</p

A single intrabulbar Aβ application impairs the ability to smell.

<p>The graph shows the time needed for control animals (injected with vehicle; white bars) and animals with intrabulbar injection of Aβ (gray bars) to reach a hidden piece of chocolate (50 mg). The horizontal axis indicates when the test was made, expressed as the number of weeks after surgery. The maximal time allowed for the search was 600 s. Note that the animals lose the ability to smell, and the loss increases with time after the Aβ injection. For these experiments the data are represented as the median and the interquartile range. * Denotes a significant difference relative to control (vehicle; p < 0.05).</p

Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory

<div><p>Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions.</p> </div

Nicotine facilitation of long-term memory depends on NMDA receptors.

<p>Training (gray columns) and escape (black columns) latencies of rats that had been treated with: A, different doses of nicotine (Nic); or C, Nic (0.4 mg/kg, same data as in A), AP5 (50 mM), or a combination of both drugs. Retention latency in the inhibitory avoidance task: B, at different doses of Nic; or D, with Nic (0.4 mg/kg, same data as in A) and 50 mM AP5 alone or in combination. For this and Figs. 4, 5, median and interquartile ranges of latency scores are depicted. *p≤0.05 vs. Control, Kruskal-Wallis, <i>post hoc</i> U-Mann-Whitnney.</p

Glial D-serine is necessary for nicotine potentiation of synaptic transmission.

<p>The EFP slope as a function of time before and after administration of nicotine (Nic, 1 µM) in combination with: D-serine (A, D-ser, 20 µM); DCKA (B, 200 nM), an antagonist of NMDA receptors at the glycine-binding site; DAAO (C, 0.1 U/ml), a specific enzyme that degrades D-serine; or D-serine in the presence of FAC (D, 5 mM). Insets, representative traces with the indicated drugs (see Fig. 1 for details). E, Summary of the experiments in A–D; data represent the mean ± S.E.M. of the EFP slope (as percent of control), after nicotine administration (see Fig. 1 for details), (*p<0.05, **p<0.01, one-way repeated-measures ANOVA, <i>post hoc</i> Fisher test).</p