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 (GluA4HC−/− 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 GluA4HC−/− 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 GluA4HC−/− 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.
Highlights
Network oscillatory patterns at different frequencies in the hippocampus represent distinct operating modes essential for normal spatial memory functions [1]
In this study we selectively reduced AMPA receptor-mediated excitatory currents onto a subset of GABAergic interneurons by ablating GluA4 in the hippocampus
It was previously shown that of the GluA4-expressing GABAergic interneurons in the CA1 region, approximately 80% express parvalbumin
Summary
Network oscillatory patterns at different frequencies in the hippocampus represent distinct operating modes essential for normal spatial memory functions [1]. Mouse mutants with reduced AMPA or NMDA receptor-mediated currents only in parvalbumin-expressing interneurons exhibited altered network oscillations together with impaired spatial working memory [18,19,20]. Because these manipulations affected interneurons in several brain regions, the phenotype could not unequivocally be linked to an alteration in hippocampal interneurons per se. Murray and colleagues [21] reported that blocking the synaptic output of parvalbumin-expressing hippocampal interneurons is sufficient to cause a severe spatial working memory impairment. The network alterations associated with such hippocampus-restricted manipulations are still unknown
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