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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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PV-positive INs express Disc 1.Confocal image stack of DAPI, PV and Disc1 stained-sections demonstrated expression of Disc1 in PV-positive neurons in the PrlC of Disc1 and control mice. Images are representative for 35 PV/Disc1-positive cells (of 39 tested PV-expressing neurons) in Disc1 PrlC and 15 PV/Disc1-positive cells (of 15 tested) in ctrl PrlC. p = 0.832. Image size: 20 µm.DOI:http://dx.doi.org/10.7554/eLife.04979.014
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fig3s2: PV-positive INs express Disc 1.Confocal image stack of DAPI, PV and Disc1 stained-sections demonstrated expression of Disc1 in PV-positive neurons in the PrlC of Disc1 and control mice. Images are representative for 35 PV/Disc1-positive cells (of 39 tested PV-expressing neurons) in Disc1 PrlC and 15 PV/Disc1-positive cells (of 15 tested) in ctrl PrlC. p = 0.832. Image size: 20 µm.DOI:http://dx.doi.org/10.7554/eLife.04979.014

Mentions: To obtain deeper insight into the pathophysiology of Disc1-associated behavioural despair, we next focussed on the mechanisms underlying impaired low-gamma oscillations in the PrlC because human depression patients show reduced low-gamma activity in frontal regions (Liu et al., 2012). Our cFos labelling suggested that TST directly activated the PrlC network (Figure 2A) and that local PrlC mechanisms may contribute to the TST phenotype of Disc1 mice. The PrlC of Disc1 mice contained significantly fewer PV-positive INs (∼40% reduction, p = 0.0037, 9 Disc1 and 8 control mice, Figure 3A, Figure 3—figure supplement 1). A similar reduction in PV-positive cells was observed in CA1 (∼40%; p = 0.022) but not in the ventro-orbital cortex (p = 0.375; Figure 3—figure supplement 1). PV-positive cells of both genotypes expressed Disc1 (Figure 3—figure supplement 2). In contrast, the number of somatostatin-expressing INs (p = 0.392) and total cell density (DAPI area, p = 0.158) were unchanged (Figure 3A,B). Studies on schizophrenia patients suggested that PV-expression might be down-regulated in FS-INs (Hashimoto et al., 2003). However, detection of PV immunoreactivity in electrophysiologically identified FS-INs in PrlC slices did not depend on the genotype (Disc1: 9/16 cells; control: 10/19 cells; Figure 3C, Figure 3—figure supplement 3). Moreover, the number of INs expressing calbindin, a marker for FS-INs partially coexpressed with PV (Markram et al., 2004), was reduced in the Disc1 PrlC in vivo (∼25% reduction, p = 0.027, 6 Disc1 and 5 control mice, Figure 3D), supporting our conclusion of reduced PV-cell quantity rather than PV content of FS-INs. Finally, the frequency of miniature IPSCs (mIPSCs) recorded in PCs was significantly reduced in the PrlC of Disc1 mice, consistent with a loss of PV-positive cells (p = 0.025, 24 Disc1 and 15 control cells; Figure 2E). These data further suggested a lack of mechanisms compensating for the reduced PV cell population.10.7554/eLife.04979.012Figure 3.Loss of FS-INs and their output synapses in the Disc1 PrlC.


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

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

PV-positive INs express Disc 1.Confocal image stack of DAPI, PV and Disc1 stained-sections demonstrated expression of Disc1 in PV-positive neurons in the PrlC of Disc1 and control mice. Images are representative for 35 PV/Disc1-positive cells (of 39 tested PV-expressing neurons) in Disc1 PrlC and 15 PV/Disc1-positive cells (of 15 tested) in ctrl PrlC. p = 0.832. Image size: 20 µm.DOI:http://dx.doi.org/10.7554/eLife.04979.014
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Related In: Results  -  Collection

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fig3s2: PV-positive INs express Disc 1.Confocal image stack of DAPI, PV and Disc1 stained-sections demonstrated expression of Disc1 in PV-positive neurons in the PrlC of Disc1 and control mice. Images are representative for 35 PV/Disc1-positive cells (of 39 tested PV-expressing neurons) in Disc1 PrlC and 15 PV/Disc1-positive cells (of 15 tested) in ctrl PrlC. p = 0.832. Image size: 20 µm.DOI:http://dx.doi.org/10.7554/eLife.04979.014
Mentions: To obtain deeper insight into the pathophysiology of Disc1-associated behavioural despair, we next focussed on the mechanisms underlying impaired low-gamma oscillations in the PrlC because human depression patients show reduced low-gamma activity in frontal regions (Liu et al., 2012). Our cFos labelling suggested that TST directly activated the PrlC network (Figure 2A) and that local PrlC mechanisms may contribute to the TST phenotype of Disc1 mice. The PrlC of Disc1 mice contained significantly fewer PV-positive INs (∼40% reduction, p = 0.0037, 9 Disc1 and 8 control mice, Figure 3A, Figure 3—figure supplement 1). A similar reduction in PV-positive cells was observed in CA1 (∼40%; p = 0.022) but not in the ventro-orbital cortex (p = 0.375; Figure 3—figure supplement 1). PV-positive cells of both genotypes expressed Disc1 (Figure 3—figure supplement 2). In contrast, the number of somatostatin-expressing INs (p = 0.392) and total cell density (DAPI area, p = 0.158) were unchanged (Figure 3A,B). Studies on schizophrenia patients suggested that PV-expression might be down-regulated in FS-INs (Hashimoto et al., 2003). However, detection of PV immunoreactivity in electrophysiologically identified FS-INs in PrlC slices did not depend on the genotype (Disc1: 9/16 cells; control: 10/19 cells; Figure 3C, Figure 3—figure supplement 3). Moreover, the number of INs expressing calbindin, a marker for FS-INs partially coexpressed with PV (Markram et al., 2004), was reduced in the Disc1 PrlC in vivo (∼25% reduction, p = 0.027, 6 Disc1 and 5 control mice, Figure 3D), supporting our conclusion of reduced PV-cell quantity rather than PV content of FS-INs. Finally, the frequency of miniature IPSCs (mIPSCs) recorded in PCs was significantly reduced in the PrlC of Disc1 mice, consistent with a loss of PV-positive cells (p = 0.025, 24 Disc1 and 15 control cells; Figure 2E). These data further suggested a lack of mechanisms compensating for the reduced PV cell population.10.7554/eLife.04979.012Figure 3.Loss of FS-INs and their output synapses 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