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The glycoprotein reelin is important for embryonic neuronal migration. During adulthood reelin possibly acts as a modulator of synaptic plasticity. Several studies link reduced levels of reelin messenger RNA and protein to the pathophysiology of certain neuropsychiatric disorders. However, little is known about reelin's role for behavioral and cognitive functions in vivo. Therefore, the effect of a reelin knockdown in the medial prefrontal cortex (mPFC) of Wistar rats was examined in behavioral tasks related to neuropsychiatric disorders, such as schizophrenia. Rats treated with reelin antisense phosphothioate oligonucleotides in the mPFC during puberty or adulthood were tested for prepulse inhibition (PPI) of the acoustic startle reflex, spatial working memory, object recognition, and locomotor activity. Reelin quantification in the mPFC was assessed by Western blotting. Local reelin knockdown during puberty or adulthood induced (1) a PPI deficit as well as (2) an impairment of spatial working memory and object recognition following pubertal injections. Western blot analyses showed a distinct and highly selective reelin knockdown in the rats' mPFC. These results indicate that mPFC reelin signaling plays an important role in behavioral tasks with relevance to e.g. schizophrenia. Understanding reelin's function as a neurotrophic modulator of the extracellular matrix may help to achieve new insights into the etiology of certain neuropsychiatric diseases and foster prospective treatment strategies.