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Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.

Caputi A, Fuchs EC, Allen K, Le Magueresse C, Monyer H - PLoS ONE (2012)

Bottom Line: Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence.These changes were associated with an increased firing rate of pyramidal cells during ripples.These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

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Local field potentials during sharp wave/ripples in GluA4HC−/− mice.(A) Representative examples of SWRs recorded during a rest trial in a control and a GluA4HC−/− mouse. Top trace: raw signal. Bottom trace: band-pass filtered (125–250 Hz) signal. (B) Mean length of SWR epochs and frequency of SWR occurrence in control and GluA4HC−/− mice. (C) Mean time-frequency representation of power centered on the peak power of each SWR epoch. (D) Mean power spectrum of SWRs in control and GluA4HC−/− mice. (E) Mean peak ripple frequency and mean peak power during SWRs in control and GluA4HC−/− mice. (F) Mean waveform of ripples centered on the peak power of each SWR epoch and aligned on the positive-to-negative zero-crossing. (G) Mean ripple amplitude in control and GluA4HC−/− mice. *: p<0.05.
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pone-0037318-g003: Local field potentials during sharp wave/ripples in GluA4HC−/− mice.(A) Representative examples of SWRs recorded during a rest trial in a control and a GluA4HC−/− mouse. Top trace: raw signal. Bottom trace: band-pass filtered (125–250 Hz) signal. (B) Mean length of SWR epochs and frequency of SWR occurrence in control and GluA4HC−/− mice. (C) Mean time-frequency representation of power centered on the peak power of each SWR epoch. (D) Mean power spectrum of SWRs in control and GluA4HC−/− mice. (E) Mean peak ripple frequency and mean peak power during SWRs in control and GluA4HC−/− mice. (F) Mean waveform of ripples centered on the peak power of each SWR epoch and aligned on the positive-to-negative zero-crossing. (G) Mean ripple amplitude in control and GluA4HC−/− mice. *: p<0.05.

Mentions: SWRs were observed principally during periods of immobility. Examples are shown in Figure 3A. The duration of SWRs was similar across genotypes (Figure 3B, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.98), but they occurred less frequently in GluA4HC−/− mice compared to controls (Figure 3B, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.015). We calculated a mean time-frequency representation of power around SWR peak power for each control and GluA4HC−/− mouse (Figure 3C). The peak power between 125 and 250 Hz was higher in GluA4HC−/− mice compared to control mice. The mean power spectrum calculated during SWRs also showed that the peak ripple power was higher in GluA4HC−/− mice (Figure 3D–E, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.01). Moreover, the peak power occurred at slower frequency in GluA4HC−/− mice compared to control mice (Figure 3D–E, p = 0.04). The mean SWR waveform centered on the peak SWR power also indicated larger ripple amplitude in GluA4HC−/− mice (Figure 3F–G, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.01).


Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity.

Caputi A, Fuchs EC, Allen K, Le Magueresse C, Monyer H - PLoS ONE (2012)

Local field potentials during sharp wave/ripples in GluA4HC−/− mice.(A) Representative examples of SWRs recorded during a rest trial in a control and a GluA4HC−/− mouse. Top trace: raw signal. Bottom trace: band-pass filtered (125–250 Hz) signal. (B) Mean length of SWR epochs and frequency of SWR occurrence in control and GluA4HC−/− mice. (C) Mean time-frequency representation of power centered on the peak power of each SWR epoch. (D) Mean power spectrum of SWRs in control and GluA4HC−/− mice. (E) Mean peak ripple frequency and mean peak power during SWRs in control and GluA4HC−/− mice. (F) Mean waveform of ripples centered on the peak power of each SWR epoch and aligned on the positive-to-negative zero-crossing. (G) Mean ripple amplitude in control and GluA4HC−/− mice. *: p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366956&req=5

pone-0037318-g003: Local field potentials during sharp wave/ripples in GluA4HC−/− mice.(A) Representative examples of SWRs recorded during a rest trial in a control and a GluA4HC−/− mouse. Top trace: raw signal. Bottom trace: band-pass filtered (125–250 Hz) signal. (B) Mean length of SWR epochs and frequency of SWR occurrence in control and GluA4HC−/− mice. (C) Mean time-frequency representation of power centered on the peak power of each SWR epoch. (D) Mean power spectrum of SWRs in control and GluA4HC−/− mice. (E) Mean peak ripple frequency and mean peak power during SWRs in control and GluA4HC−/− mice. (F) Mean waveform of ripples centered on the peak power of each SWR epoch and aligned on the positive-to-negative zero-crossing. (G) Mean ripple amplitude in control and GluA4HC−/− mice. *: p<0.05.
Mentions: SWRs were observed principally during periods of immobility. Examples are shown in Figure 3A. The duration of SWRs was similar across genotypes (Figure 3B, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.98), but they occurred less frequently in GluA4HC−/− mice compared to controls (Figure 3B, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.015). We calculated a mean time-frequency representation of power around SWR peak power for each control and GluA4HC−/− mouse (Figure 3C). The peak power between 125 and 250 Hz was higher in GluA4HC−/− mice compared to control mice. The mean power spectrum calculated during SWRs also showed that the peak ripple power was higher in GluA4HC−/− mice (Figure 3D–E, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.01). Moreover, the peak power occurred at slower frequency in GluA4HC−/− mice compared to control mice (Figure 3D–E, p = 0.04). The mean SWR waveform centered on the peak SWR power also indicated larger ripple amplitude in GluA4HC−/− mice (Figure 3F–G, control n = 9 mice, GluA4HC−/− n = 12 mice, p = 0.01).

Bottom Line: Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence.These changes were associated with an increased firing rate of pyramidal cells during ripples.These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.

Show MeSH
Related in: MedlinePlus