Sex steroids are neuromodulators that play a crucial role in learning, memory, and synaptic plasticity, providing circuit flexibility and dynamic functional connectivity in mammals. Previous studies indicate that testosterone is crucial for neuronal functions and required further investigation on various frontiers. However, it is surprising to note that studies on testosterone-induced neurotrophin-4 (NT-4) expression and its influence on synaptic plasticity and learning and memory moderation are scanty. The present study is focused on analysing the localized influence of NT-4 on hippocampal synaptic plasticity and associated moderation in learning and memory under testosterone deprivation. Adult Wistar albino rats were randomly divided into various groups, control (Cont), orchidectomy (ORX), ORX + testosterone supplementation (ORX + T), and Cont + testosterone (Cont + T). After 2 weeks, the serum testosterone level was undetectable in ORX rats. The behavioural assessment showed a decline in the learning ability of ORX rats with increased working and reference memory errors in the behavioural assessment in the 8-arm radial maze. The mRNA and protein expressions of NT-4 and androgen receptors (ARs) were significantly reduced in the ORX group. In addition, there was a decrease in the number of neuronal dendrites in Golgi-Cox staining. These changes were not seen in ORX + T rats with improved learning behaviour indicating that testosterone exerts its protective effect on hippocampal synaptic plasticity through AR-dependent NT-4 regulation in learning and memory upgrade.

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