Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels

Abstract

Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

Keywords: CD4 T cells; OT-II transgenic mice; Th2 cytokines; adult neurogenesis; cognition.

Fig. 1.

Behavioral tests to determine cognitive function. (A) Novel object recognition test: Discrimination index of OT-II mice was significantly less than that for control mice in the test session, whereas discrimination indices of both groups in the familiarization ession were not different. (B) Y-maze: OT-II mice showed significantly less spontaneous alternation than control mice. Values are expressed as the mean ± SEM ^*p < 0.05, and ^** p < 0.01 as compared to the control mice.

Fig. 2.

OT-II mice showed decreased neurogenesis and synaptic density in hippocampus. (A) Representative images of Ki67 staining of the DG. (B) DCX-positive cells were significantly less abundant in OT-II mice than in control mice. (C) Immunoreactivity of synaptophysin in the CA3 subfields (SL: stratum lucidum; SR: stratum radiatum) of the hippocampus was markedly less abundant in OT-II mice than in the control mice. (D) Immunoreactivity of synaptophysin in the CA1 subfields (SR: stratum radiatum; SO: stratum oriens) of the hippocampus. There was no difference between OT-II mice and control mice. Values are expressed as the mean ± SEM ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001 as compared to the control mice. Scale bar = 50 μm.

Fig. 3.

Altered levels of Th2 cytokines in OT-II mice. (A, B) Levels of peripheral Th2 cytokines released by naïve ovalbumin-specific T cells were significantly higher in OT-II mice than for control mice. (C) OT-II mice expressed significantly higher level of IL-4 in the brain than control mice. Values are expressed as the mean ± SEM ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001 as compared to the control mice.

Fig. 4.

Effects of IL-4 on the proliferation of cultured adult rat hippocampal NSCs. (A) Dose-dependency and time-course of IL-4-induced inhibition of cell proliferation. (B) NSCs were treated with 10 ng/ml IL-4 for 6, 24, 48, and 74 h. Data are mean ± SEM. ^*p <0.05 versus vehicle-treated cells.

Fig. 5.

Confirmation of inhibitory effect of IL-4 on the proliferation of cultured adult rat hippocampal NSCs. Band intensity of western blot indicated that the expression of PCNA in adult rat hippocampal NPCs was reduced after treatment of 10 ng/ml of IL-4 for 24 h. Data are mean ± SEM. ^*p < 0.05 versus vehicle-treated cells.

Fig. 6.

The proposed mechanisms for how excessive Th2 cytokines can impair the cognitive function in OT-II mice.