Low concentrations of ketamine and memantine did not affect LTP in the mouse hippocampal CA1 region, while higher concentrations of ketamine and memantine inhibited LTP.

<p><b>A,</b> Effects of different concentrations of ketamine (1 μM; 10 μM; 30 μM) on LTP. Baseline of fEPSP (normalized to the average value of baseline) was recorded for 30 min followed by TBS (indicated by the arrow), and another 1 hr fEPSP was recorded after induction. Ketamine was applied before the baseline recording. <b>Insets,</b> representative fEPSP traces of 5 min before TBS (solid curve) over fEPSP traces of 55–60 min (dotted curve) after TBS for control group (upper) and 10 μM ketamine group (lower). <b>B,</b> Summarized data showing average slope change (normalized to baseline value) of the last 20 min recordings from each group. <b>C,</b> Effects of different concentrations of memantine (1 μM; 10 μM; 30 μM) on LTP. Memantine was applied before the baseline recording. <b>Insets,</b> representative fEPSP traces for control group (upper) and 10 μM memantine group (lower). <b>D,</b> Summarized data showing average slope change (normalized to baseline value) of the last 20 min recordings from each group. All data are expressed as mean ± SEM; **p<0.01, ***p<0.001, NS, no significant difference.</p

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD

<div><p>NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer’s disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs’ therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 μM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations.</p></div

Ketamine did not affect the power of gamma oscillations but affected CA3-CA1 coherence under interface recording configuration.

<p><b>A,</b> Representative field potential recordings in CA3 from control and different ketamine concentration groups after 90 min of 100 nM kainate treatment. Ketamine was applied 60min after kainate application. <b>B,</b> group data of normalized gamma band change in CA3 region with or without ketamine treatment. <b>C,</b> group data of normalized CA3-CA1 coherence change with or without ketamine treatment. 1 μM ketamine and its control, left; 10 μM ketamine and its control, middle; 30 μM ketamine and its control, right. All data are expressed as mean ± SEM.</p

cLTD reduced hippocampal gamma oscillations and this reduction was prevented by 10 μM ketamine.

<p><b>A,</b> The scheme is for the recording of both LTD and gamma oscillations in a hippocampal slice, ketamine was added at the beginning of the experiment (the unfilled horizontal bar). <b>B1, B2, B3, B4,</b> Representative recordings from one slice of control group (B1); LTD group (B2); LTD+1 μM ketamine group (B3); LTD+10 μM ketamine group (B4). Each column includes trace of evoked fEPSP (upper row), local field potential in CA1 (middle row) and power spectrum analysis of oscillations (lower row) from one slice respectively. Upper, representative fEPSP traces (parallel time point for control group) over averaged fEPSP of the last 20 min recording; middle, example local field potential traces showing oscillatory activity 20 min after kainate application from the same slices; lower, power spectrum of oscillations on the same slices at the same time point. <b>C,</b> Time-course of normalized fEPSP slope (normalized to baseline value) showing the control recording; LTD induction and the effects of 1 μM and 10 μM on NMDA-induced LTD. 5 min of 20 μM NMDA perfusion was indicated by the bar for LTD groups. <b>D,</b> Summarized data showing average slope change (normalized to baseline value) of the last 10 min recordings for control group, 1 μM ketamine group, 10 μM ketamine group, LTD group, LTD+1 μM ketamine group, LTD+10 μM ketamine group. <b>E,</b> Averaged power spectrum of 30 sec oscillations after 20 min of kainate application in control group, LTD group, LTD+1 μM ketamine group, LTD+10 μM ketamine group. <b>F,</b> Summarized data showing total power of 15–80 Hz oscillations in control group, LTD group, LTD+1 μM ketamine group, LTD+10 μM ketamine group. All data are expressed as mean ± SEM; *p<0.05, ***p<0.001.</p

Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration

<div><p>To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.</p></div

Prepulse Inhibition of the Acoustic Startle Reflex in fbΔBMPRII Mice.

<p>The fbΔBMPRII mutants (red) and control littermates (white) showed similar levels of prepulse inhibition of the acoustic startle across three different intensities of the prepulse stimulus. Thus, the mutant mice did not show deficits in sensorimotor gating.</p

Western Blot Analysis of BMPRII Protein in the Brain.

<p>Western blot analysis of tissues from the hippocampus (HP), Cerebellum (Cb), and cortex (Cx) in BMPRII flox/flox controls (cn) and BMPRII flox/flox; CaMKIIα-Cre (ko) mice. At 2 months old, fbΔBMPRII mutant mice show a great reduction of BMPRII protein in the hippocampus and cortex, but show similar levels of BMPRII protein in the cerebellum.</p

Loss of Smad4 Modulates Anxiety-Related Behavior in the Elevated Plus Maze.

<p>In the Elevated Plus Maze (A) the fbΔSmad4 mutant mice (blue) spent a significantly increased proportion of time exploring the open-arms, (B) had a significantly increased duration of time on the open-arms, (C) and made significantly more entries onto the open-arms compared to control littermates (white). When closed-arm exploration was examined, (D) the fbΔSmad4 mutant mice spent a significantly reduced proportion of time on the closed-arms, but (E) there was no significant difference in duration of time on the closed-arms, however, (F) the number of closed-arm entries was significantly reduced. Results reported as mean ± S.E.M. Asterisk indicates *p<0.05.</p

Loss of BMPRII Modulates Anxiety-Related Behavior in the Elevated Plus Maze.

<p>In the Elevated Plus Maze (A) the fbΔBMPRII mutant mice (red) spent a significantly increased proportion of time exploring the open-arms compared to control littermates (white), and (B) had a significantly increased duration of time on the open-arms, (C) but there was no significant difference in open-arm entries. When closed-arm exploration was examined, (D) the fbΔBMPRII mutant mice spent a significantly reduced proportion of time on the closed-arms, and (E) had a significantly reduced duration of time on the closed-arms, (F) but there was no significant difference in closed-arm entries. Results reported as mean ± S.E.M. Asterisk indicates *p<0.05 or **p<0.005.</p

Floating Behavior in the Water Maze and Immobility of BMPRII Mice in the Porsolt Swim Test.

<p>(A) The fbΔBMPRII mutant mice (red) had significantly more trials with floating behavior during the water maze compared to control littermates, (B) and significantly more trials with floating across days, which impacted the average swimming speed of the mice, as well as the latency to find the hidden platform. (C) When tested in the PST, the fbΔBMPRII mutants did not have any differences in immobility compared to littermate controls, (D) and did not have any differences in the latency to first bout of immobility. Results reported as mean ± S.E.M. Asterisk indicates *p<0.05, **p<0.005.</p