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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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Recording depths and axonal distance between pairs of synaptically connected neurons are similar in Disc1 and control FS-IN to PC recordings.(A) Amplitude of uIPSCs is plotted against distance of the recorded soma from the pial surface. Broken line indicates border between layer 2/3 and 5. There is no correlation between uIPSC amplitude and the anatomical depth of the presynaptic (left) or postsynaptic (right) neuron in FS-IN to PC paired recordings in acute prefrontal slices. (B) Synaptic latency was defined as the time between the maximal point of rise of the presynaptic action potential and the onset of the postsynaptic uIPSC. Paired recordings in Disc1 and control slices show similar mean synaptic latencies (Disc1: 1.0 ± 0.03 ms vs control 1.0 ± 0.05 ms, p = 0.379, n = 19 Disc1, 13 control pairs), suggesting similar axonal distance between pre- and postsynaptic partners under the assumption of similar conduction velocities of action potentials and similar transmitter release periods. (C) Failure rate did not depend on the distance (expressed as synaptic latency) between pre- and postsynaptic cells (r = −0.04, p = 0.825). Bars represent mean ± SEM, circles represent individual data points.DOI:http://dx.doi.org/10.7554/eLife.04979.018
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fig4s1: Recording depths and axonal distance between pairs of synaptically connected neurons are similar in Disc1 and control FS-IN to PC recordings.(A) Amplitude of uIPSCs is plotted against distance of the recorded soma from the pial surface. Broken line indicates border between layer 2/3 and 5. There is no correlation between uIPSC amplitude and the anatomical depth of the presynaptic (left) or postsynaptic (right) neuron in FS-IN to PC paired recordings in acute prefrontal slices. (B) Synaptic latency was defined as the time between the maximal point of rise of the presynaptic action potential and the onset of the postsynaptic uIPSC. Paired recordings in Disc1 and control slices show similar mean synaptic latencies (Disc1: 1.0 ± 0.03 ms vs control 1.0 ± 0.05 ms, p = 0.379, n = 19 Disc1, 13 control pairs), suggesting similar axonal distance between pre- and postsynaptic partners under the assumption of similar conduction velocities of action potentials and similar transmitter release periods. (C) Failure rate did not depend on the distance (expressed as synaptic latency) between pre- and postsynaptic cells (r = −0.04, p = 0.825). Bars represent mean ± SEM, circles represent individual data points.DOI:http://dx.doi.org/10.7554/eLife.04979.018

Mentions: To test whether altered synaptic transmission of local FS-INs might contribute to the low-gamma defect, we recorded from layer 5 FS-INs and PCs in acute prefrontal slices (Figure 4). Paired recordings from synaptically connected FS-INs and postsynaptic PCs revealed a strong reduction in the amplitude of unitary inhibitory postsynaptic currents (uIPSCs) in Disc1 PrlC (∼60% reduction, p = 0.012, 20 and 13 pairs, respectively; Figure 4A). This decline in synaptic inhibition was not caused by a reduced connection probability with distance among communicating partners because inter-somatic distances between pre- and postsynaptic cells were identical (<60 µm; see ‘Material and methods’; Figure 4—figure supplement 1).10.7554/eLife.04979.017Figure 4.Output and input signalling of FS-INs are impaired in the Disc1 PrlC.


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

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

Recording depths and axonal distance between pairs of synaptically connected neurons are similar in Disc1 and control FS-IN to PC recordings.(A) Amplitude of uIPSCs is plotted against distance of the recorded soma from the pial surface. Broken line indicates border between layer 2/3 and 5. There is no correlation between uIPSC amplitude and the anatomical depth of the presynaptic (left) or postsynaptic (right) neuron in FS-IN to PC paired recordings in acute prefrontal slices. (B) Synaptic latency was defined as the time between the maximal point of rise of the presynaptic action potential and the onset of the postsynaptic uIPSC. Paired recordings in Disc1 and control slices show similar mean synaptic latencies (Disc1: 1.0 ± 0.03 ms vs control 1.0 ± 0.05 ms, p = 0.379, n = 19 Disc1, 13 control pairs), suggesting similar axonal distance between pre- and postsynaptic partners under the assumption of similar conduction velocities of action potentials and similar transmitter release periods. (C) Failure rate did not depend on the distance (expressed as synaptic latency) between pre- and postsynaptic cells (r = −0.04, p = 0.825). Bars represent mean ± SEM, circles represent individual data points.DOI:http://dx.doi.org/10.7554/eLife.04979.018
© Copyright Policy
Related In: Results  -  Collection

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

fig4s1: Recording depths and axonal distance between pairs of synaptically connected neurons are similar in Disc1 and control FS-IN to PC recordings.(A) Amplitude of uIPSCs is plotted against distance of the recorded soma from the pial surface. Broken line indicates border between layer 2/3 and 5. There is no correlation between uIPSC amplitude and the anatomical depth of the presynaptic (left) or postsynaptic (right) neuron in FS-IN to PC paired recordings in acute prefrontal slices. (B) Synaptic latency was defined as the time between the maximal point of rise of the presynaptic action potential and the onset of the postsynaptic uIPSC. Paired recordings in Disc1 and control slices show similar mean synaptic latencies (Disc1: 1.0 ± 0.03 ms vs control 1.0 ± 0.05 ms, p = 0.379, n = 19 Disc1, 13 control pairs), suggesting similar axonal distance between pre- and postsynaptic partners under the assumption of similar conduction velocities of action potentials and similar transmitter release periods. (C) Failure rate did not depend on the distance (expressed as synaptic latency) between pre- and postsynaptic cells (r = −0.04, p = 0.825). Bars represent mean ± SEM, circles represent individual data points.DOI:http://dx.doi.org/10.7554/eLife.04979.018
Mentions: To test whether altered synaptic transmission of local FS-INs might contribute to the low-gamma defect, we recorded from layer 5 FS-INs and PCs in acute prefrontal slices (Figure 4). Paired recordings from synaptically connected FS-INs and postsynaptic PCs revealed a strong reduction in the amplitude of unitary inhibitory postsynaptic currents (uIPSCs) in Disc1 PrlC (∼60% reduction, p = 0.012, 20 and 13 pairs, respectively; Figure 4A). This decline in synaptic inhibition was not caused by a reduced connection probability with distance among communicating partners because inter-somatic distances between pre- and postsynaptic cells were identical (<60 µm; see ‘Material and methods’; Figure 4—figure supplement 1).10.7554/eLife.04979.017Figure 4.Output and input signalling of FS-INs are impaired 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