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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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Identical dynamic and kinetic properties of uIPSCs at FS-IN output synapses.(A) Paired-pulse modulation in FS-IN-to-PC paired recordings was was determined from dual pulse stimulation (inter-pulse interval 20 or 50 ms) in paired recordings. Two presynaptic action potentials were evoked in the FS-IN at 20 ms and 50 ms inter-pulse interval. Amplitudes of uIPSCs were measured from the preceding baseline and the paired-pulse ratio (uIPSC2/uIPSC1) was quantified. (B) Summary of paired-pulse experiments show no significant difference in short-term dynamics of uIPSCs between both genotypes (20 ms, p = 0.836, n = 7 Disc1, 6 control pairs, 50 ms, p = 0.037, n = 6, 6). (C and D) Analysis of multiple-pulse modulation of uIPSCs elicited by trains of action potentials (10 pulses, 50 Hz) in paired recordings revealed identical modulation across genotypes (10th uIPSC/1st uIPSC, p = 0.671, n = 8, 7). (E) Determination of kinetic properties of uIPSCs. The solid lines represent biexponential fits to the decay phase of the average uIPSC. (F) Neither the 20–80% rise time (p = 0.985, n = 19, 13) nor the decay time constant (p = 0.193, n = 10, 11) differed between genotypes. Inner graphs shows the amplitude-scaled fits to the decay phase shown in E. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.020
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fig4s3: Identical dynamic and kinetic properties of uIPSCs at FS-IN output synapses.(A) Paired-pulse modulation in FS-IN-to-PC paired recordings was was determined from dual pulse stimulation (inter-pulse interval 20 or 50 ms) in paired recordings. Two presynaptic action potentials were evoked in the FS-IN at 20 ms and 50 ms inter-pulse interval. Amplitudes of uIPSCs were measured from the preceding baseline and the paired-pulse ratio (uIPSC2/uIPSC1) was quantified. (B) Summary of paired-pulse experiments show no significant difference in short-term dynamics of uIPSCs between both genotypes (20 ms, p = 0.836, n = 7 Disc1, 6 control pairs, 50 ms, p = 0.037, n = 6, 6). (C and D) Analysis of multiple-pulse modulation of uIPSCs elicited by trains of action potentials (10 pulses, 50 Hz) in paired recordings revealed identical modulation across genotypes (10th uIPSC/1st uIPSC, p = 0.671, n = 8, 7). (E) Determination of kinetic properties of uIPSCs. The solid lines represent biexponential fits to the decay phase of the average uIPSC. (F) Neither the 20–80% rise time (p = 0.985, n = 19, 13) nor the decay time constant (p = 0.193, n = 10, 11) differed between genotypes. Inner graphs shows the amplitude-scaled fits to the decay phase shown in E. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.020

Mentions: To determine which of the synaptic parameters, number of release sites (Nr), quantal size (Qr) and release probability (Pr), may contribute to the reduction in uIPSC size, we used multiple probability-compound binomial analysis (Kraushaar and Jonas, 2000) (Figure 4B,C). Nr but not Qr or Pr was reduced in Disc1 pairs by ∼60% (p = 0.036, p = 0.831, p = 0.178, 14 and 11 pairs, respectively; Figure 4C). Bootstrapping demonstrated that errors in the parameter estimation were similar to previous reports (Kraushaar and Jonas, 2000) (Figure 4—figure supplement 2). Failure rate and coefficient of variation of uIPSCs were higher in Disc1 pairs (p = 0.015 and p = 0.008, respectively; Figure 4—figure supplement 1), whereas the skewness was unchanged (p = 0.503, Figure 4D), confirming a change in Nr rather than Pr (Kerr et al., 2008). Paired-pulse behaviour and kinetic properties of uIPSCs did not depend on the genotype, further excluding altered Pr or somatodendritic synapse location, respectively (Figure 4—figure supplement 3). Amplitudes of quantal IPSCs recorded in the presence of extracellular 5.5 mM strontium were not significantly different between genotypes (4 and 5 pairs; p = 0.195). Moreover, mIPSCs had similar mean size in PCs located in the PrlC of Disc1 and control mice, further confirming similar Qr (24 and 15 cells, p = 0.388; Figure 4—figure supplement 4). Thus, Disc1 FS-INs form ∼60% fewer release sites per target PC, resulting in an according reduction of unitary inhibitory strength. How can the contradiction between similar numbers of axonal release sites per FS-IN but fewer synaptic contacts per FS-IN-to-PC connection in Disc1 PrlC be reconciled? Interestingly, connection probability defined as the probability to record from connected FS-IN-to-PC pairs was ∼threefold higher in Disc1 mice (Disc1: 35.4%, control: 11.5%, p < 0.001; Figure 4A), suggesting that redistribution of release sites at the expense of individual connection strength might contribute to low-gamma defects.


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

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

Identical dynamic and kinetic properties of uIPSCs at FS-IN output synapses.(A) Paired-pulse modulation in FS-IN-to-PC paired recordings was was determined from dual pulse stimulation (inter-pulse interval 20 or 50 ms) in paired recordings. Two presynaptic action potentials were evoked in the FS-IN at 20 ms and 50 ms inter-pulse interval. Amplitudes of uIPSCs were measured from the preceding baseline and the paired-pulse ratio (uIPSC2/uIPSC1) was quantified. (B) Summary of paired-pulse experiments show no significant difference in short-term dynamics of uIPSCs between both genotypes (20 ms, p = 0.836, n = 7 Disc1, 6 control pairs, 50 ms, p = 0.037, n = 6, 6). (C and D) Analysis of multiple-pulse modulation of uIPSCs elicited by trains of action potentials (10 pulses, 50 Hz) in paired recordings revealed identical modulation across genotypes (10th uIPSC/1st uIPSC, p = 0.671, n = 8, 7). (E) Determination of kinetic properties of uIPSCs. The solid lines represent biexponential fits to the decay phase of the average uIPSC. (F) Neither the 20–80% rise time (p = 0.985, n = 19, 13) nor the decay time constant (p = 0.193, n = 10, 11) differed between genotypes. Inner graphs shows the amplitude-scaled fits to the decay phase shown in E. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.020
© Copyright Policy
Related In: Results  -  Collection

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

fig4s3: Identical dynamic and kinetic properties of uIPSCs at FS-IN output synapses.(A) Paired-pulse modulation in FS-IN-to-PC paired recordings was was determined from dual pulse stimulation (inter-pulse interval 20 or 50 ms) in paired recordings. Two presynaptic action potentials were evoked in the FS-IN at 20 ms and 50 ms inter-pulse interval. Amplitudes of uIPSCs were measured from the preceding baseline and the paired-pulse ratio (uIPSC2/uIPSC1) was quantified. (B) Summary of paired-pulse experiments show no significant difference in short-term dynamics of uIPSCs between both genotypes (20 ms, p = 0.836, n = 7 Disc1, 6 control pairs, 50 ms, p = 0.037, n = 6, 6). (C and D) Analysis of multiple-pulse modulation of uIPSCs elicited by trains of action potentials (10 pulses, 50 Hz) in paired recordings revealed identical modulation across genotypes (10th uIPSC/1st uIPSC, p = 0.671, n = 8, 7). (E) Determination of kinetic properties of uIPSCs. The solid lines represent biexponential fits to the decay phase of the average uIPSC. (F) Neither the 20–80% rise time (p = 0.985, n = 19, 13) nor the decay time constant (p = 0.193, n = 10, 11) differed between genotypes. Inner graphs shows the amplitude-scaled fits to the decay phase shown in E. Data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.04979.020
Mentions: To determine which of the synaptic parameters, number of release sites (Nr), quantal size (Qr) and release probability (Pr), may contribute to the reduction in uIPSC size, we used multiple probability-compound binomial analysis (Kraushaar and Jonas, 2000) (Figure 4B,C). Nr but not Qr or Pr was reduced in Disc1 pairs by ∼60% (p = 0.036, p = 0.831, p = 0.178, 14 and 11 pairs, respectively; Figure 4C). Bootstrapping demonstrated that errors in the parameter estimation were similar to previous reports (Kraushaar and Jonas, 2000) (Figure 4—figure supplement 2). Failure rate and coefficient of variation of uIPSCs were higher in Disc1 pairs (p = 0.015 and p = 0.008, respectively; Figure 4—figure supplement 1), whereas the skewness was unchanged (p = 0.503, Figure 4D), confirming a change in Nr rather than Pr (Kerr et al., 2008). Paired-pulse behaviour and kinetic properties of uIPSCs did not depend on the genotype, further excluding altered Pr or somatodendritic synapse location, respectively (Figure 4—figure supplement 3). Amplitudes of quantal IPSCs recorded in the presence of extracellular 5.5 mM strontium were not significantly different between genotypes (4 and 5 pairs; p = 0.195). Moreover, mIPSCs had similar mean size in PCs located in the PrlC of Disc1 and control mice, further confirming similar Qr (24 and 15 cells, p = 0.388; Figure 4—figure supplement 4). Thus, Disc1 FS-INs form ∼60% fewer release sites per target PC, resulting in an according reduction of unitary inhibitory strength. How can the contradiction between similar numbers of axonal release sites per FS-IN but fewer synaptic contacts per FS-IN-to-PC connection in Disc1 PrlC be reconciled? Interestingly, connection probability defined as the probability to record from connected FS-IN-to-PC pairs was ∼threefold higher in Disc1 mice (Disc1: 35.4%, control: 11.5%, p < 0.001; Figure 4A), suggesting that redistribution of release sites at the expense of individual connection strength might contribute to low-gamma defects.

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