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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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Similar fluctuation of spEPSCs at Disc1 and control FS-IN inputs.Superimposed individual spEPSCs are shown for a representative FS-IN recording in Disc1 and control PrlC slices. Note the similar variability in the amplitude of the input spEPSCs, quantified as the coefficient of variation (p = 0.596, n = 15, 9 cells).DOI:http://dx.doi.org/10.7554/eLife.04979.022
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fig4s5: Similar fluctuation of spEPSCs at Disc1 and control FS-IN inputs.Superimposed individual spEPSCs are shown for a representative FS-IN recording in Disc1 and control PrlC slices. Note the similar variability in the amplitude of the input spEPSCs, quantified as the coefficient of variation (p = 0.596, n = 15, 9 cells).DOI:http://dx.doi.org/10.7554/eLife.04979.022

Mentions: Recruitment of FS-INs by local excitatory collaterals is an important requirement for the generation of gamma oscillations (Tiesinga and Sejnowski, 2009). We therefore examined FS-IN excitation by glutamatergic synapses (Figure 4E,F). The frequency of spontaneous excitatory postsynaptic current (spEPSC) was strongly reduced (p = 0.022, 15 Disc1 and 9 control cells). In contrast the mean amplitude and coefficient of variation of spEPSCs were unchanged (p = 0.34 and p = 0.596, respectively; Figure 4E,F, Figure 4—figure supplement 5), suggesting reduced PC-to-FS-IN connectivity rather than changes in Nr, Qr or Pr. SpEPSC frequency in PCs was unaffected (Figure 4E,F). Thus, synaptic excitation particularly of FS-INs is impaired and may contribute to low-gamma defects in Disc1 PrlC.


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

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

Similar fluctuation of spEPSCs at Disc1 and control FS-IN inputs.Superimposed individual spEPSCs are shown for a representative FS-IN recording in Disc1 and control PrlC slices. Note the similar variability in the amplitude of the input spEPSCs, quantified as the coefficient of variation (p = 0.596, n = 15, 9 cells).DOI:http://dx.doi.org/10.7554/eLife.04979.022
© Copyright Policy
Related In: Results  -  Collection

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

fig4s5: Similar fluctuation of spEPSCs at Disc1 and control FS-IN inputs.Superimposed individual spEPSCs are shown for a representative FS-IN recording in Disc1 and control PrlC slices. Note the similar variability in the amplitude of the input spEPSCs, quantified as the coefficient of variation (p = 0.596, n = 15, 9 cells).DOI:http://dx.doi.org/10.7554/eLife.04979.022
Mentions: Recruitment of FS-INs by local excitatory collaterals is an important requirement for the generation of gamma oscillations (Tiesinga and Sejnowski, 2009). We therefore examined FS-IN excitation by glutamatergic synapses (Figure 4E,F). The frequency of spontaneous excitatory postsynaptic current (spEPSC) was strongly reduced (p = 0.022, 15 Disc1 and 9 control cells). In contrast the mean amplitude and coefficient of variation of spEPSCs were unchanged (p = 0.34 and p = 0.596, respectively; Figure 4E,F, Figure 4—figure supplement 5), suggesting reduced PC-to-FS-IN connectivity rather than changes in Nr, Qr or Pr. SpEPSC frequency in PCs was unaffected (Figure 4E,F). Thus, synaptic excitation particularly of FS-INs is impaired and may contribute to low-gamma defects in 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