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. 2013 May;16(4):857-67.
doi: 10.1017/S1461145712000703. Epub 2012 Aug 29.

Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours

Ming Guo  1 , Tung-Yi Huang, Jacob C Garza, Streamson C Chua, Xin-Yun Lu
Affiliations

Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours

Ming Guo et al. Int J Neuropsychopharmacol. 2013 May.

Abstract

Previous studies have demonstrated that leptin and its receptors (LepRb) in the central nervous system play an important role in regulating depression- and anxiety-related behaviours. However, the physiological functions of LepRb in specific brain regions for mediating different emotional behaviours remain to be defined. In this study, we examined the behavioural effects of LepRb ablation in the adult hippocampus using a series of behavioural paradigms for assessing depression- and anxiety-related behaviours. Targeted deletion of LepRb was achieved using the Cre/loxP site-specific recombination system through bilateral stereotaxic delivery of an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the dentate gyrus of adult mice homozygous for a floxed leptin receptor allele. AAV-Cre-mediated deletion of the floxed region of LepRb was detected 2 wk after injection. In accordance with this, leptin-stimulated phosphorylation of Akt was attenuated in the hippocampus of AAV-Cre injected mice. Mice injected with AAV-Cre displayed normal locomotor activity and anxiety-like behaviour, as determined in the elevated plus-maze, light-dark box and open field tests, but showed increased depression-like behaviours in the tail suspension, saccharin preference and learned helplessness tests. Taken together, these data suggest that deletion of LepRb in the adult hippocampus is sufficient to induce depression-like behaviours. Our results support the view that leptin signalling in the hippocampus may be essential for positive mood states and active coping to stress.

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Conflict of interest statement

INTEREST STATEMENT

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Deletion of LepRb in the adult hippocampus. A. Schematic diagrams showing design of the AAV-Cre-GFP (upper) and AAV-GFP (lower) constructs. B. GFP expression in the dentate gyrus. Low magnification image (top, left) shows GFP distribution restricted in the dentate gyrus. Higher magnification (top, right and bottom). C. RT-PCR analysis of LepRb exon 17 mRNA in the hippocampus. Hipp, hippocampus; Hyp, hypothalamus. D. Western blot analysis. Hippocampal lysates from AAV-Cre-GFP and AAV-GFP injected mice were immunoblotted for total AKT and AKT phosphorylated on Thr308. n = 4. *P < 0.05, compared to aCSF treatment.
Figure 2
Figure 2
Body weight gain and food intake in mice with deletion of LepRb in the dentate gyrus of adult male mice. A. Body weight was monitored at different time points after stereotaxic injection of AAV-Cre-GFP or AAV-GFP vectors into the dentate gyrus. B. Food intake was measured for 5 days at 3 weeks after intra-dentate gyrus injection of AAV-Cre-GFP and AAV-GFP vectors. Average food intake per day was calculated. n = 11–12 per group. Data are presented as mean ± SEM.
Figure 3
Figure 3
Locomotor activity after LepRb deletion. Male mice injected with either AAV-Cre-GFP or AAV-GFP in the dentate gyrus exhibited a similar level of locomotor activity during the testing period whether analyzed as 2 minute increments or total distance traveled over the entire 30 min period. n = 8–9 per group. Data are presented as mean ± SEM.
Figure 4
Figure 4
Anxiety levels in mice with deletion of LepRb in the dentate gyrus. A. The elevated plus maze. Left, the percentage of time spent in the open arms/total time spent in all arms. Right, the percentage of entries made into the open arms/total entries made into all arms. n = 9–10 per group. B. The light/dark choice. Left, the time spent in the light compartment. Right, the number of transitions between light and dark compartments. n = 9–10 per group. C. The open field test. Left, the time spent in the center area. Right, the total distance traveled in the entire open field. n = 10 per group. Data are presented as mean ± SEM.
Figure 5
Figure 5
AAV-Cre-induced LepRb deletion in the adult dentate gyrus results in depression-like behavior. A. Tail suspension test. Immobility time was measured during the 6-min test period. n = 11 per group. **P < 0.01 compared to AAV-GFP treatment. B. Forced swim test. Immobility time was measured during the last 4 min of the 6-min test period. n = 8–10 per group. C. Saccharin preference was expressed as a ratio of the volume of saccharin solution intake to the volume of water intake for a 4-day test. n = 11 per group. *P < 0.05 compared to AAV-GFP treatment. D. Performance in the learned helplessness test. Left, mean escape latencies in six blocks of five trials. Right, number of failures to escape over the 30 trials. n = 9–12 per group. *P < 0.05, **P < 0.01, compared with the AAV-GFP, Shock control group. Data are presented as mean ± SEM.
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