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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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Additional assessment of working memory performance.(A) Working memory assessment in a delayed match-to-place task in the water y-maze. In each trial, animals had to find the hidden platform in one of the target arms (sample phase). After a 30 s delay, the mice were released from the same start arm (match phase) and could either choose the correct arm or the opposite arm (working memory error). Both Disc1 and control mice performed significantly better in the match phase, indicating intact spatial working memory (n = 6, 10). (B) Both genotypes showed similar spontaneous alternation when they explored a y-maze for 10 min, confirming intact working memory (n = 8 each group). #p < 0.001. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.004
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fig1s1: Additional assessment of working memory performance.(A) Working memory assessment in a delayed match-to-place task in the water y-maze. In each trial, animals had to find the hidden platform in one of the target arms (sample phase). After a 30 s delay, the mice were released from the same start arm (match phase) and could either choose the correct arm or the opposite arm (working memory error). Both Disc1 and control mice performed significantly better in the match phase, indicating intact spatial working memory (n = 6, 10). (B) Both genotypes showed similar spontaneous alternation when they explored a y-maze for 10 min, confirming intact working memory (n = 8 each group). #p < 0.001. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.004

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)

Additional assessment of working memory performance.(A) Working memory assessment in a delayed match-to-place task in the water y-maze. In each trial, animals had to find the hidden platform in one of the target arms (sample phase). After a 30 s delay, the mice were released from the same start arm (match phase) and could either choose the correct arm or the opposite arm (working memory error). Both Disc1 and control mice performed significantly better in the match phase, indicating intact spatial working memory (n = 6, 10). (B) Both genotypes showed similar spontaneous alternation when they explored a y-maze for 10 min, confirming intact working memory (n = 8 each group). #p < 0.001. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.004
© Copyright Policy
Related In: Results  -  Collection

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

fig1s1: Additional assessment of working memory performance.(A) Working memory assessment in a delayed match-to-place task in the water y-maze. In each trial, animals had to find the hidden platform in one of the target arms (sample phase). After a 30 s delay, the mice were released from the same start arm (match phase) and could either choose the correct arm or the opposite arm (working memory error). Both Disc1 and control mice performed significantly better in the match phase, indicating intact spatial working memory (n = 6, 10). (B) Both genotypes showed similar spontaneous alternation when they explored a y-maze for 10 min, confirming intact working memory (n = 8 each group). #p < 0.001. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.004
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