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Impaired fast-spiking interneuron function in a genetic mouse model of depression.

Sauer JF, Strüber M, Bartos M - Elife (2015)

Bottom Line: The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets.Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations.Our data link network defects with a gene mutation underlying depression in humans.

View Article: PubMed Central - PubMed

Affiliation: Physiologisches Institut I, Systemic and Cellular Neurophysiology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.

ABSTRACT
Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans.

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Unchanged hippocampal-prefrontal theta coherence.(A) Average coherence during TST and baseline revealed a sharp peak in the delta frequency range in both genotypes. Solid lines are mean, shaded areas SEM. (B) There is no difference in the average coherence (6–12 Hz) between Disc1 and control mice (n = 4 Disc1, 3 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.010
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fig2s1: Unchanged hippocampal-prefrontal theta coherence.(A) Average coherence during TST and baseline revealed a sharp peak in the delta frequency range in both genotypes. Solid lines are mean, shaded areas SEM. (B) There is no difference in the average coherence (6–12 Hz) between Disc1 and control mice (n = 4 Disc1, 3 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.010

Mentions: In humans and rodents activity in the PrlC becomes synchronized during various behavioural states (Uhlhaas and Singer, 2010; Roux et al., 2012). We therefore speculated that Disc1 truncation might cause changes in rhythmic activity patterns rather than gross activity levels in the PrlC. To test for this possibility, we recorded local field potentials (LFPs) in the PrlC of behaving mice (Figure 2B). Longer freeze times of Disc1 mice were apparent in the electrode-implanted sample (8 Disc1 and 6 control mice, p = 0.0041; Figure 2B) similar to non-implanted Disc1 mice. During TST, Disc1 mice showed reduced normalized power and amplitude in the theta (6–12 Hz, p = 0.012 and p = 0.001, respectively) and low-gamma (30–50 Hz, p = 0.003 and p = 0.002, respectively) but not high gamma band (80–100 Hz, p = 0.11 and p = 0.239, respectively; Figure 2C–E). Oscillations were similarly impaired during home cage exploration (Figure 2F). These observations were independent of the behavioral state and present during movement and passive coping (Figure 2—figure supplement 1). When data from Disc1 and control mice were pooled, theta and low-gamma power linearly correlated with freeze duration in TST (thetaTST p = 0.0061 and low-gammaTST p = 0.0007, respectively; Figure 2G, left) but not with immobility in the home cage (thetabaseline p = 0.829 and low-gammabaseline p = 0.782, respectively; Figure 2G, right), showing that reduced synchrony of theta and low-gamma oscillations impairs TST-specific cortical processing rather than alterations in general locomotion. Moreover, low-gamma but not theta power in the home cage could significantly predict TST freeze duration when Disc1 and control data were pooled (p = 0.033, p = 0.114, respectively; Figure 2H), indicating that local low-gamma power correlates with defects of the intrinsic function of the prefrontal network irrespective of the animal's behaviour. Recordings of spontaneous low-gamma oscillations during UP states under anaesthesia (Hasenstaub et al., 2005) confirmed the independence of low-gamma power from behaviour-dependent brain state (Figure 2I). Jointly these data suggest that defective thetaTST and low-gammaTST+baseline are correlated with behavioural despair of Disc1 mice.


Impaired fast-spiking interneuron function in a genetic mouse model of depression.

Sauer JF, Strüber M, Bartos M - Elife (2015)

Unchanged hippocampal-prefrontal theta coherence.(A) Average coherence during TST and baseline revealed a sharp peak in the delta frequency range in both genotypes. Solid lines are mean, shaded areas SEM. (B) There is no difference in the average coherence (6–12 Hz) between Disc1 and control mice (n = 4 Disc1, 3 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.010
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374525&req=5

fig2s1: Unchanged hippocampal-prefrontal theta coherence.(A) Average coherence during TST and baseline revealed a sharp peak in the delta frequency range in both genotypes. Solid lines are mean, shaded areas SEM. (B) There is no difference in the average coherence (6–12 Hz) between Disc1 and control mice (n = 4 Disc1, 3 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.010
Mentions: In humans and rodents activity in the PrlC becomes synchronized during various behavioural states (Uhlhaas and Singer, 2010; Roux et al., 2012). We therefore speculated that Disc1 truncation might cause changes in rhythmic activity patterns rather than gross activity levels in the PrlC. To test for this possibility, we recorded local field potentials (LFPs) in the PrlC of behaving mice (Figure 2B). Longer freeze times of Disc1 mice were apparent in the electrode-implanted sample (8 Disc1 and 6 control mice, p = 0.0041; Figure 2B) similar to non-implanted Disc1 mice. During TST, Disc1 mice showed reduced normalized power and amplitude in the theta (6–12 Hz, p = 0.012 and p = 0.001, respectively) and low-gamma (30–50 Hz, p = 0.003 and p = 0.002, respectively) but not high gamma band (80–100 Hz, p = 0.11 and p = 0.239, respectively; Figure 2C–E). Oscillations were similarly impaired during home cage exploration (Figure 2F). These observations were independent of the behavioral state and present during movement and passive coping (Figure 2—figure supplement 1). When data from Disc1 and control mice were pooled, theta and low-gamma power linearly correlated with freeze duration in TST (thetaTST p = 0.0061 and low-gammaTST p = 0.0007, respectively; Figure 2G, left) but not with immobility in the home cage (thetabaseline p = 0.829 and low-gammabaseline p = 0.782, respectively; Figure 2G, right), showing that reduced synchrony of theta and low-gamma oscillations impairs TST-specific cortical processing rather than alterations in general locomotion. Moreover, low-gamma but not theta power in the home cage could significantly predict TST freeze duration when Disc1 and control data were pooled (p = 0.033, p = 0.114, respectively; Figure 2H), indicating that local low-gamma power correlates with defects of the intrinsic function of the prefrontal network irrespective of the animal's behaviour. Recordings of spontaneous low-gamma oscillations during UP states under anaesthesia (Hasenstaub et al., 2005) confirmed the independence of low-gamma power from behaviour-dependent brain state (Figure 2I). Jointly these data suggest that defective thetaTST and low-gammaTST+baseline are correlated with behavioural despair of Disc1 mice.

Bottom Line: The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets.Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations.Our data link network defects with a gene mutation underlying depression in humans.

View Article: PubMed Central - PubMed

Affiliation: Physiologisches Institut I, Systemic and Cellular Neurophysiology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.

ABSTRACT
Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans.

Show MeSH
Related in: MedlinePlus