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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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Extra-dimensional rule-shifting task in the y-maze.(A) Mice were food-restricted and learned to forage in a y-maze. Then, they learned the first reward rule (right arm correct). In each trial, one randomly chosen arm of the two possible target arms was illuminated. Once the animals had learned the spatial rule, the reward regime was changed to ‘light on’ (extradimensional shift, n = 6, 5). (B) Normalized correct trials are plotted against trial number. Arrow at t = 0 indicates the reward rule change. Both groups of mice learned the initial spatial rule as well as the rule change. Data are binned over 10 runs. (C) Examples of individual learning curves of a Disc1 and a control mouse with 95% confidence intervals. The trial in which the lower confidence interval exceeded chance level was considered the first trial in which the animal had learned the task (learning trial). Right, identical learning trials of both rules in Disc1 and control mice. Data are mean ± SEM unless stated.DOI:http://dx.doi.org/10.7554/eLife.04979.005
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fig1s2: Extra-dimensional rule-shifting task in the y-maze.(A) Mice were food-restricted and learned to forage in a y-maze. Then, they learned the first reward rule (right arm correct). In each trial, one randomly chosen arm of the two possible target arms was illuminated. Once the animals had learned the spatial rule, the reward regime was changed to ‘light on’ (extradimensional shift, n = 6, 5). (B) Normalized correct trials are plotted against trial number. Arrow at t = 0 indicates the reward rule change. Both groups of mice learned the initial spatial rule as well as the rule change. Data are binned over 10 runs. (C) Examples of individual learning curves of a Disc1 and a control mouse with 95% confidence intervals. The trial in which the lower confidence interval exceeded chance level was considered the first trial in which the animal had learned the task (learning trial). Right, identical learning trials of both rules in Disc1 and control mice. Data are mean ± SEM unless stated.DOI:http://dx.doi.org/10.7554/eLife.04979.005

Mentions: To test for schizophrenia-associated symptoms we assessed context representation and learning (Waters et al., 2004) and examined spatial reference and working memory in the radial arm water maze (Murray et al., 2011). Both groups showed identical spatial learning and numbers of working memory errors (Figure 1E–G). We confirmed intact working memory of Disc1 mice in a delayed match-to-sample and a spontaneous alternation task (Figure 1—figure supplement 1). Furthermore, Disc1 mice could normally learn reward rules in a spatial extra-dimensional paradigm-shifting task (Figure 1—figure supplement 2). This test resembles features of the Wisonsin card sorting test, in which schizophrenia patients typically show deficits (Okubo et al., 1997). Finally, Disc1 mice had no abnormalities in anxiety or sociability (Figure 1—figure supplements 3, 4). Thus, Disc1 mice showed a specific phenotype broadly interpreted as depression-related behavioural despair (Porsolt et al., 1977; Steru et al., 1985).


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

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

Extra-dimensional rule-shifting task in the y-maze.(A) Mice were food-restricted and learned to forage in a y-maze. Then, they learned the first reward rule (right arm correct). In each trial, one randomly chosen arm of the two possible target arms was illuminated. Once the animals had learned the spatial rule, the reward regime was changed to ‘light on’ (extradimensional shift, n = 6, 5). (B) Normalized correct trials are plotted against trial number. Arrow at t = 0 indicates the reward rule change. Both groups of mice learned the initial spatial rule as well as the rule change. Data are binned over 10 runs. (C) Examples of individual learning curves of a Disc1 and a control mouse with 95% confidence intervals. The trial in which the lower confidence interval exceeded chance level was considered the first trial in which the animal had learned the task (learning trial). Right, identical learning trials of both rules in Disc1 and control mice. Data are mean ± SEM unless stated.DOI:http://dx.doi.org/10.7554/eLife.04979.005
© Copyright Policy
Related In: Results  -  Collection

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

fig1s2: Extra-dimensional rule-shifting task in the y-maze.(A) Mice were food-restricted and learned to forage in a y-maze. Then, they learned the first reward rule (right arm correct). In each trial, one randomly chosen arm of the two possible target arms was illuminated. Once the animals had learned the spatial rule, the reward regime was changed to ‘light on’ (extradimensional shift, n = 6, 5). (B) Normalized correct trials are plotted against trial number. Arrow at t = 0 indicates the reward rule change. Both groups of mice learned the initial spatial rule as well as the rule change. Data are binned over 10 runs. (C) Examples of individual learning curves of a Disc1 and a control mouse with 95% confidence intervals. The trial in which the lower confidence interval exceeded chance level was considered the first trial in which the animal had learned the task (learning trial). Right, identical learning trials of both rules in Disc1 and control mice. Data are mean ± SEM unless stated.DOI:http://dx.doi.org/10.7554/eLife.04979.005
Mentions: To test for schizophrenia-associated symptoms we assessed context representation and learning (Waters et al., 2004) and examined spatial reference and working memory in the radial arm water maze (Murray et al., 2011). Both groups showed identical spatial learning and numbers of working memory errors (Figure 1E–G). We confirmed intact working memory of Disc1 mice in a delayed match-to-sample and a spontaneous alternation task (Figure 1—figure supplement 1). Furthermore, Disc1 mice could normally learn reward rules in a spatial extra-dimensional paradigm-shifting task (Figure 1—figure supplement 2). This test resembles features of the Wisonsin card sorting test, in which schizophrenia patients typically show deficits (Okubo et al., 1997). Finally, Disc1 mice had no abnormalities in anxiety or sociability (Figure 1—figure supplements 3, 4). Thus, Disc1 mice showed a specific phenotype broadly interpreted as depression-related behavioural despair (Porsolt et al., 1977; Steru et al., 1985).

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