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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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Morphological characteristics of FS-INs.(A) Axon reconstructions of FS-INs revealed dense axonal plexus. Asterisks mark som position (not shown). (B) FS-INs form perisomatic boutons on their target cells. Asterisks indicate soma positions of putative PCs. This example is depicted from a control mouse. (C) Disc1 and control FS-INs had similar total axon lengths. Data are mean ± SEM. n = 4 cells each group.DOI:http://dx.doi.org/10.7554/eLife.04979.016
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fig3s4: Morphological characteristics of FS-INs.(A) Axon reconstructions of FS-INs revealed dense axonal plexus. Asterisks mark som position (not shown). (B) FS-INs form perisomatic boutons on their target cells. Asterisks indicate soma positions of putative PCs. This example is depicted from a control mouse. (C) Disc1 and control FS-INs had similar total axon lengths. Data are mean ± SEM. n = 4 cells each group.DOI:http://dx.doi.org/10.7554/eLife.04979.016

Mentions: The loss of FS-INs was paired with an equal reduction in the number of their PV/VGAT-coexpressing terminals (∼40% reduction, p = 0.021, 6 Disc1 and 4 control mice, Figure 3F). Three-dimensional reconstructions of FS-INs revealed no difference in bouton density on FS-IN axons (Figure 3G). Similarly, we detected comparable bouton densities on PV-positive axons in the PrlC of both genotypes in vivo (Figure 3G) and indistinguishable axon lengths from reconstructed cells in vitro (Figure 3—figure supplement 4). Thus, the amount of PV-positive FS-INs and their synapses is reduced by ∼40% in the Disc1 PrlC.


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

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

Morphological characteristics of FS-INs.(A) Axon reconstructions of FS-INs revealed dense axonal plexus. Asterisks mark som position (not shown). (B) FS-INs form perisomatic boutons on their target cells. Asterisks indicate soma positions of putative PCs. This example is depicted from a control mouse. (C) Disc1 and control FS-INs had similar total axon lengths. Data are mean ± SEM. n = 4 cells each group.DOI:http://dx.doi.org/10.7554/eLife.04979.016
© Copyright Policy
Related In: Results  -  Collection

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

fig3s4: Morphological characteristics of FS-INs.(A) Axon reconstructions of FS-INs revealed dense axonal plexus. Asterisks mark som position (not shown). (B) FS-INs form perisomatic boutons on their target cells. Asterisks indicate soma positions of putative PCs. This example is depicted from a control mouse. (C) Disc1 and control FS-INs had similar total axon lengths. Data are mean ± SEM. n = 4 cells each group.DOI:http://dx.doi.org/10.7554/eLife.04979.016
Mentions: The loss of FS-INs was paired with an equal reduction in the number of their PV/VGAT-coexpressing terminals (∼40% reduction, p = 0.021, 6 Disc1 and 4 control mice, Figure 3F). Three-dimensional reconstructions of FS-INs revealed no difference in bouton density on FS-IN axons (Figure 3G). Similarly, we detected comparable bouton densities on PV-positive axons in the PrlC of both genotypes in vivo (Figure 3G) and indistinguishable axon lengths from reconstructed cells in vitro (Figure 3—figure supplement 4). Thus, the amount of PV-positive FS-INs and their synapses is reduced by ∼40% in the Disc1 PrlC.

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