Knockdown of α2C-adrenoceptors in the occipital cortex rescued long-term potentiation in hidden prenatally malnourished rats

Moderate reduction in the protein content of the mother’s diet calorically compensated by carbohydrates (the so-called “hidden” prenatal malnutrition) leads to increased neocortical expression of the α2C-adrenoceptor subtype, together with decreased cortical release of noradrenaline and impaired long-term potentiation (LTP) and visuospatial memory performance during the rat postnatal life. Ín order to study whether overexpression of the α2C-adrenoceptor subtype is causally related to the decreased indices of neocortical plasticity found in prenatally malnourished rats, we evaluated the effect of intracortical (occipital cortex) administration of an antisense oligodeoxynucleotide (ODN) raised against the α2C-adrenoceptor mRNA on the LTP elicited in vivo in the occipital cortex of hidden prenatally malnourished rats. In addition, we compare the effect of the antisense ODN to that produced by systemical administration of the subtype-nonselective α2-adrenoceptor antagonist atipamezole. Prenatal protein malnutrition led to impaired occipital cortex LTP together with increased expression of α2C-adrenoceptors (about twice Bmax) in the same cortical region. [3H]-rauwolscine binding assay showed that a 7-day intracortical antisense ODN treatment in the malnourished rats resulted in 50% knockdown of α2C-adrenoceptor expression and, in addition, completely rescued the ability of the occipital cortex to develop and maintain long-term potentiation. Atipamezole (0.3 mg/kg i.p.) also led to full recovery of neocortical LTP in malnourished rats. The present results argue in favor of our original hypothesis that the deleterious effect of prenatal malnutrition on neocortical plasticity in the adult progeny is in part consequence of increased neocortical α2C-adrenoceptor expression. This receptor subtype is known to be involved in the presynaptic control of noradrenaline release from central neurons, a neurotransmitter that critically influences LTP and memory formation.

► Prenatal malnutrition led to overexpressed α2C-adrenoceptors in rat occipital cortex.
► Prenatally malnourished rats also showed impaired occipital cortex LTP.
► Antisense ODN targeting of α2C-adrenoceptors fully rescued occipital cortex LTP.
► The α2-adrenoceptor antagonist atipamezole also led to recovering of defective LTP.
► α2C-Adrenoceptor overexpression is causally related to LTP deficits in malnutrition.