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. 2006 Nov 14;103(46):17501-6.
doi: 10.1073/pnas.0607207103. Epub 2006 Nov 6.

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Michael D Saxe  1 , Fortunato Battaglia, Jing-Wen Wang, Gael Malleret, Denis J David, James E Monckton, A Denise R Garcia, Michael V Sofroniew, Eric R Kandel, Luca Santarelli, René Hen, Michael R Drew
Affiliations

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Michael D Saxe et al. Proc Natl Acad Sci U S A. .

Abstract

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Irradiation impairs contextual but not cued fear conditioning. (A-C) Schematic diagram of the fear conditioning procedure (n = 14 per group). (A) Day 1: training (context A). (B) Day 2: cued test (context B). (C) Day 3: context test (context A). (D) Conditioned freezing during the tone test. Percent time freezing during the 60 s before tone presentation (pretone) and during the 20-s tone presentation (Tone). Data were subjected to a 2 (treatment) × 2 (period: pretone vs. tone) ANOVA (n = 14 per group). Mice froze significantly more during the tone than during the pretone period [F(1,26) = 38.7, P < 0.001]. There was no effect of X irradiation [F(1,26) = 0.3] and no treatment × period interaction [F(1,26) < 1]. (E) Percent time freezing during the 4 min of the context test. Data were subjected to a 2 (treatment) × 4 (minute) ANOVA. Irradiated mice spent significantly less time freezing than sham mice [F(1,26) = 5.4, P = 0.03]. Error bars represent ± 1 SEM.
Fig. 2.
Fig. 2.
GCV treatment impairs contextual but not cued fear conditioning in GFAP-TK TG mice. (A) Conditioned freezing during the tone test. Percent of time freezing during the 60 s before tone presentation (pretone) and during the 20-s tone presentation (tone) is shown. Data were subjected to a 2 (treatment) × 2 (period: pretone vs. tone) ANOVA [n = 19 (WT) and 11 (TG)]. Mice froze significantly more during the tone than during the pretone period [F(1,28) = 14.1, P < 0.001]. There was no effect of genotype [F(1,28) = 0.5] or genotype × period interaction [F(1,28) < 1]. (B) Percent time freezing during the 4 min of the context test. Data were subjected to a 2 (treatment) × 4 (minute) ANOVA. Irradiated mice spent significantly less time freezing than did sham mice [F(1,28) = 4.7, P = 0.04].
Fig. 3.
Fig. 3.
Ablation of neurogenesis prevents a form of LTP in the DG. Slices for physiological experiments were derived either 3 months after x-ray treatment (A-C) or immediately after a 6-week GCV treatment was completed (D-F). (A) MPP/DG LTP in sham (n = 8) and irradiated (n = 8) mice 3 months after treatment. Arrow indicates the delivery of the 100-Hz stimulation. Repeated-measures ANOVA performed on the last 10 min of recording confirmed a significant difference between sham and x-irradiated animals [F(1,14) = 11.2, P < 0.001]. (B) LTP evoked in the DG after the addition of 50 μM picrotoxin. Stimulation parameters are the same as above. There is no difference in LTP between sham and irradiated mice [F(1,14) < 1]. (C) LTP in the Schaffer collateral to CA1 connection was not altered by irradiation [F(1,14) < 1]. (D) Six weeks of GCV treatment caused a loss of LTP in the DG in TG (n = 9) but not WT (n = 15) mice. Repeated measures ANOVA on the last 10 min confirmed a significant difference between WT and TG animals [F(1,24) = 7.2, P = 0.01]. (E) GCV treatment did not alter DG LTP elicited in the presence of 50 μM picrotoxin [F(1,24) < 1]. (F) LTP in Schaffer collateral/CA1 connections was also unaffected by GCV [F(1,24) < 1]. Error bars represent ± 1 SEM.
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