Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory

Abstract

Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

Figure 1

Selective expression of TeLC in parvalbumin-positive interneurons of the hippocampus. (a) AAV construct and recombination sequence for Cre-dependent TeLC expression. The coding region is inverted between sets of heterotypic anti-parallel loxP sites. Cre inverts the coding region (1) and locks it in the correct orientation (2). CBA, CMV enhancer/chicken β-actin promoter. (b) After injection of AAV-FLEX-TeLC into CA1 of Pvalb-cre mice, TeLC selectively blocks transmitter release in parvalbumin-positive neurons. All other neurons are unaffected (PV, parvalbumin; SV, synaptic vesicle). (c) Immunostaining for TeLC in a coronal section of an AAV-FLEX-TeLC–injected Pvalb-cre brain. DG, dentate gyrus. Scale bar represents 500 μm. (d–f) Magnification of boxed area in c showing parvalbumin expression (d), TeLC expression (e) and their colocalization (f). Scale bar represents 50 μm. (g,h) Percentages of TeLC-expressing parvalbumin-positive cells along the rostro-caudal CA1 axis (g) and in different hippocampal subfields (h). (i) Fraction of TeLC-positive cells in different parvalbumin-positive interneuron subpopulations. Som, somatostatin; St. oriens, stratum oriens; St. pyram, stratum pyramidale. Data are mean ± s.e.m. All procedures involving experimental mice were in accordance with the UK Animals (Scientific Procedures) Act 1986 and approved by the Ethical Review Committee of the University of Aberdeen.

Figure 2

Blocking parvalbumin-positive cell–mediated inhibition in the hippocampus impairs spatial working but not reference memory. (a) Recording configuration. Scale bar represents 100 μm. (b) Magnification of boxed area in a. Immunostaining revealed strong TeLC expression in putative parvalbumin-positive terminals. Scale bar represents 5 μm. (c) Average IPSCs evoked during control conditions (black) and during WIN55,212 (orange). (d) Summary graph of normalized eIPSC peak amplitudes during WIN55,212. ***P < 0.001. (e) Both CA1-PV-TeLC and CA1-PV-GFP mice acquired the platform location in the RAWM as indicated by a reduction in path length. (f) CA1-PV-TeLC mice made significantly more working memory errors over the 5 d of training. (g) Delayed matching to sample/place task. CA1-PV-TeLC mice were not different from controls in sample trials (white bars), but did not improve in match trials (gray bars). Data are mean ± s.e.m. *P < 0.05.