Antidepressant-like Effects of Peripheral Reelin Administration in a Preclinical Model of Depression
Mitchell, Milann A. L. 1992-
Depression is a serious psychiatric disorder characterized by a range of debilitating symptoms. Long-term exposure to stress is a significant risk factor for the onset and maintenance of depression. Rats exposed to repeated treatment with the stress hormone corticosterone (CORT), a well-established rodent model of depression, begin to display depression-like symptoms. The development of depression-like symptoms with prolonged exposure to CORT is accompanied by reductions in the number and maturation rate of immature dentate granule cells within the hippocampus. Furthermore, these changes are paralleled by gradual decreases in reelin-expressing cells in the dentate subgranular zone of the hippocampus. Reelin is a large extracellular matrix protein that has been implicated in a number of neuropsychiatric disorders, including szchiphrenia, bipolar disorder, autism, as well as major depression. It holds important roles in learning and memory, cell migration and integration, synaptic contact formation, and adult neurogenesis. Mice deficient in reelin are more susceptible to CORT-induced impairments in hippocampal neurogenesis and the development of a depressive phenotype. Previous work has shown that intra-hippocampal infusions of reelin into the hippocampus reverse CORT-induced increases in depression-like behavior in rats, while restoring accompanying impairments in hippocampal neurogenesis. Reelin is also expressed in peripheral organs and tissues, though its roles here are not well understood. However, reelin-deficient mice show peripheral alterations in the clustering pattern of the serotonin transporter (SERT) in membranes of blood lymphocytes. The serotonin transporter is one of the main targets of antidepressant action, and importantly, this altered pattern of SERT clustering in reelin-deficient mice is mirrored both in patients with depression and in rats exposed to prolonged CORT treatment. Based on the previous findings, we were motivated to examine whether peripheral injections of reelin could restore CORT-induced increases in depression-like behavior. To investigate possible mechanisms, we examined (i) the SERT clustering pattern in peripheral lymphocyte membranes, and (ii) the maturation rate of immature hippocampal neurons. 40mg/kg of CORT was administered subcutaneously once per day for 21 consecutive days. In conjunction, we utilized a novel reelin injection paradigm, where reelin was delivered via the lateral tail vein at either 3μg/ml or 5μg/ml every 5 or 10 days during the period of CORT injections. Depression-like behavior was measured using the forced swim test the day following the last CORT injection. The open field test was included as a measure of locomotive and anxiety-like behavior. Importantly, peripheral reelin at all dosages administered restored CORT-induced increases in depression-like behavior in the forced swim test, normalizing both immobility and swimming behaviors. Neither CORT nor reelin impacted open field behavior. As expected, CORT-treated rats displayed alterations in SERT membrane protein clustering, and importantly this was restored by all doses of reelin administered. Peripheral reelin did not significantly reverse the CORT-induced deficits in immature neuron maturation rate. These novel findings demonstrate that reelin has antidepressant-like actions when given peripherally and provide evidence for the regulation of serotonin transporter clustering in lymphocyte membranes as a mechanism for the antidepressant action of reelin.
DegreeMaster of Arts (M.A.)
CommitteeLaPrairie, Robert; Howland, John; Prime, Steven; Gagnon, Michelle
Copyright DateDecember 2017
membrane protein clustering