Duration-dependent hippocampal GLUT4 upregulation mediates depressive and cognitive deficits in rats with propylthiouracil-induced hypothyroidism

INTRODUCTION: Adult-onset hypothyroidism can cause emotional and memory impairment. However, the underlying mechanism remainsunclear. This study aimed to investigate the effect of short-term hypothyroidism on the expression of GLUT4 in the hippocampus of adultrats and to elucidate the bridging role of abnormal GLUT4 in key brain regions and to explore its potential role in mood and cognitiveimpairment in hypothyroidism. MATERIAL AND METHODS: Thirty male Wistar rats were divided into a control group (n = 10), propylthiouracil (PTU)-induced hypothyroid groups (PTU6W/10W/14W, n = 5 each), and PTU14W + levothyroxine (LT4, n = 5). Behavioral tests (open field, novel object recognition,Morris water maze) assessed emotional and cognitive functions. Serum thyroid hormones, glucose, insulin, and hippocampal GLUT4expression [Western blot, quantitative polymerase chain reaction (qPCR), immunohistochemistry] were analyzed. RESULTS: Hypothyroid rats exhibited reduced body weight, serum triiodothyronine (T3), thyroxine (T4), glucose, and insulin (p < 0.05), with elevated thyroid-stimulating hormone (TSH). Behavioral deficits emerged progressively: PTU6W showed depressive-like behaviors(50% decrease in open field locomotion); PTU10W/14W displayed impaired novel object recognition (30% lower discrimination index);PTU14W had prolonged water maze latency (2-fold increase) and 40% shorter platform quadrant duration. Hippocampal GLUT4 proteinincreased time-dependently (1.8-fold in PTU14W vs. control, p < 0.05), while GLUT4 messenger RNA (mRNA) remained unchanged.Levothyroxine reversed these effects. CONCLUSIONS: Short-term hypothyroidism induces depressive-like behaviors, whereas prolonged deficiency exacerbates spatial memory deficits. Compensatory GLUT4 protein upregulation, potentially mediated by insulin signaling, may sustain glucose metabolism duringearly hypothyroidism. However, chronic impairment overwhelms this adaptation, triggering cognitive decline. Dynamic GLUT4 regulation plays a pivotal role in hypothyroidism-related cognitive dysfunction.