RESUMO
Impaired glutamate recycling plays an important role in the pathophysiology of depression, and it has been demonstrated that glutamate transporter-1 (GLT-1) on astrocytes is involved in glutamate uptake. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, however, the exact mechanism of rTMS treatment remains unclear. Here, we used a chronic unpredictable mild stress (CUMS) protocol to induce depression-like behaviors in rats followed by rTMS treatment. Behavioral assessment was primarily through SPT, FST, OFT and body weight. Histological analysis focused on GFAP and GLT-1 expression, synaptic plasticity, apoptosis and PI3K/Akt/CREB pathway-related proteins. The results showed that rTMS treatment increased sucrose preference, improved locomotor activity, shortened immobility time as well as increased body weight. And rTMS intervention reversed the elevated glutamate concentration in the hippocampus of CUMS rats using an ELISA kit. Moreover, rTMS ameliorated the reduction in GFAP and GLT-1 expression, alleviated the decrease in BDNF, PSD95 and synapsin-1 expression, also reversed the expression levels of BAX and Bcl2 in the hippocampus of CUMS-induced rats. Moreover, rTMS also increased the protein phosphorylation level of PI3K/Akt/CREB pathway. These results suggest that rTMS treatment ameliorates depression-like behaviors in the rat model by reversing the reduction of GLT-1 on astrocytes and reducing glutamate accumulation in the synaptic cleft, which in turn ameliorates synaptic plasticity damage and neuronal apoptosis. The regulation of GLT-1 by rTMS may be through the PI3K/Akt/CREB pathway.
Assuntos
Ácido Glutâmico , Estimulação Magnética Transcraniana , Ratos , Animais , Ácido Glutâmico/metabolismo , Estimulação Magnética Transcraniana/métodos , Astrócitos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Depressão/metabolismo , Peso Corporal , Hipocampo/metabolismo , Estresse Psicológico/terapiaRESUMO
High-frequency repetitive transcranial magnetic stimulation (rTMS) is a widely used and effective biological treatment for depression. Although previous studies have shown that astrocyte function may be modified by rTMS, the specific neurobiological mechanisms underlying its antidepressant action are not clear. Substantial evidence has accumulated indicating that neurotrophin dysfunction and neuronal apoptosis play a role in the development of depression. To evaluate this hypothesis, we applied a chronical unpredictable mild stress (CUMS) protocol to induce depression-like behaviors in rats, followed by the delivery of 10-Hz rTMS for 3 weeks. Behavioral outcome measures consisted of a sucrose preference test, forced swimming test, and open field test. Histological analysis focused on apoptosis, expression of GFAP and FGF2, and FGF2 pathway-related proteins. The results showed that after rTMS treatment, the rats' sucrose preference increased, open field performance improved while the immobility time of forced swimming decreased. The behavioral changes seen in rTMS treated rats were accompanied by marked reductions in the number of TUNEL-positive neural cells and the level of expression of BAX and by an increase in Bcl2. Furthermore, the expression of GFAP and FGF2 was increased, along with activation of FGF2 downstream pathway. These results suggest that rTMS treatment can improve depression-like behavior, attenuate neural apoptosis, and reverse reduction of astrocytes in a rat model of depression. We hypothesize that the therapeutic action of rTMS in CUMS-induced rats is linked to the activation of the FGF2/FGFR1/p-ERK signaling pathway.