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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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Related in: MedlinePlus

Low-gamma defect in the PrlC of Disc1 mice does not depend on the behavioral state during TST.(A) Average power spectral density in the PrlC of Disc1 (green) and control mice (black) during freezing (left) and movement (right). (B) Summary plots of mean low-gamma power revelas significantly impaired power during both behavioral states. (n = 8 Disc1, 6 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.011
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fig2s2: Low-gamma defect in the PrlC of Disc1 mice does not depend on the behavioral state during TST.(A) Average power spectral density in the PrlC of Disc1 (green) and control mice (black) during freezing (left) and movement (right). (B) Summary plots of mean low-gamma power revelas significantly impaired power during both behavioral states. (n = 8 Disc1, 6 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.011

Mentions: We next examined the mechanisms underlying oscillatory impairments in Disc1 PrlC. Prefrontal theta oscillations are driven by the hippocampus (Siapas et al., 2005; Sigurdsson et al., 2010) whereas gamma activity patterns are generated by synaptic interactions between GABAergic FS-INs and glutamatergic PCs in local neuronal networks (Atallah and Scanziani, 2009; Tiesinga and Sejnowski, 2009). Consistent with the hippocampal drive of theta oscillations to the PrlC, cross-correlation analysis of theta-filtered signals in simultaneous LFP recordings from dorsal CA1 and PrlC revealed a ∼30 ms peak time lag in both Disc1 and control mice (Figure 2J). In agreement with the intact working memory of Disc1 mice, for which high synchrony of theta oscillations between hippocampus and prefrontal cortex is required (Jones and Wilson, 2005; Siapas et al., 2005; Sigurdsson et al., 2010), coherence in the theta band was comparable between genotypes (Figure 2—figure supplement 2). However, theta power was markedly reduced in CA1 of Disc1 mice (Figure 2J), suggesting that the prefrontal theta power deficit may be caused by a theta dysfunction in the hippocampus.


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

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

Low-gamma defect in the PrlC of Disc1 mice does not depend on the behavioral state during TST.(A) Average power spectral density in the PrlC of Disc1 (green) and control mice (black) during freezing (left) and movement (right). (B) Summary plots of mean low-gamma power revelas significantly impaired power during both behavioral states. (n = 8 Disc1, 6 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.011
© Copyright Policy
Related In: Results  -  Collection

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

fig2s2: Low-gamma defect in the PrlC of Disc1 mice does not depend on the behavioral state during TST.(A) Average power spectral density in the PrlC of Disc1 (green) and control mice (black) during freezing (left) and movement (right). (B) Summary plots of mean low-gamma power revelas significantly impaired power during both behavioral states. (n = 8 Disc1, 6 control mice). Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.011
Mentions: We next examined the mechanisms underlying oscillatory impairments in Disc1 PrlC. Prefrontal theta oscillations are driven by the hippocampus (Siapas et al., 2005; Sigurdsson et al., 2010) whereas gamma activity patterns are generated by synaptic interactions between GABAergic FS-INs and glutamatergic PCs in local neuronal networks (Atallah and Scanziani, 2009; Tiesinga and Sejnowski, 2009). Consistent with the hippocampal drive of theta oscillations to the PrlC, cross-correlation analysis of theta-filtered signals in simultaneous LFP recordings from dorsal CA1 and PrlC revealed a ∼30 ms peak time lag in both Disc1 and control mice (Figure 2J). In agreement with the intact working memory of Disc1 mice, for which high synchrony of theta oscillations between hippocampus and prefrontal cortex is required (Jones and Wilson, 2005; Siapas et al., 2005; Sigurdsson et al., 2010), coherence in the theta band was comparable between genotypes (Figure 2—figure supplement 2). However, theta power was markedly reduced in CA1 of Disc1 mice (Figure 2J), suggesting that the prefrontal theta power deficit may be caused by a theta dysfunction in the hippocampus.

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