Mild prenatal protein malnutrition increases α_2C‐adrenoceptor density in the cerebral cortex during postnatal life and impairs neocortical long‐term potentiation and visuo‐spatial performance in rats

Abstract

Mild reduction in the protein content of the mother's diet from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but leads to significant enhancements in the concentration and release of cortical noradrenaline during early postnatal life. Since central noradrenaline and some of its receptors are critically involved in long-term potentiation (LTP) and memory formation, this study evaluated the effect of mild prenatal protein malnutrition on the a 2C -adrenoceptor density in the frontal and occipital cortices, induction of LTP in the same cortical regions and the visuo-spatial memory. Pups born from rats fed a 25% casein diet throughout pregnancy served as controls. At day 8 of postnatal age, prenatally malnourished rats showed a threefold increase in neocortical a 2C -adrenoceptor density. At 60 days-of-age, a 2C -adrenoceptor density was still elevated in the neocortex, and the animals were unable to maintain neocortical LTP and presented lower visuo-spatial memory performance. Results suggest that overexpression of neocortical a 2C -adrenoceptors during postnatal life, subsequent to mild prenatal protein malnutrition, could functionally affect the synaptic networks subserving neocortical LTP and visuo-spatial memory formation. Keywords: a 2C adrenoceptor, long-term potentiation, neocortex, protein malnutrition, visuo-spatial memory. Central nervous system noradrenaline critically influences long-term potentiation (LTP) in cerebral cortex (Nowicky et al. 1992;Kamatsu 1996) and hippocampus (Hopkins and Johnston 1988;Radisavljevic et al. 1994;Bramham et al. 1997), as well as memory formation (Sternberg et al. 1986;Crowe et al. 1990;Gibbs 1991), through balanced activation of specific receptors. For instance, animal studies have revealed that b adrenoceptor activation is associated with enhancement of LTP in the hippocampus (Hopkins and Johnston 1988;Radisavljevic et al. 1994;Bramham et al. 1997) and memory facilitation (Crowe et al. 1990;Gibbs 1991;Gibbs and Summers 2000), while activation of a 2 adrenoceptors (Sara and Devauges 1989;Devauges and Sara 1990;Bunsey and Strupp 1995), especially the a 2C subtype (Haapalinna et al. 1998 Björklund et al. 1998Björklund et al. , 1999Björklund et al. , 2000, is related to decreased memory formation. This role of b and a 2C adrenoceptors is consistent with the widespread distribution of these receptor subtypes in the hippocampus and the cerebral cortex (Lee et al. 1998;Gibbs and Summers 2000).It has been reported that perinatal malnutrition and severe forms of prenatal malnutrition in the rat, in addition to decrease body and brain weights of pups results in functional changes of central noradrenergic systems, including increased activity of brain tyrosine hydroxylase

Long-Term Effect of Early Protein Malnutrition on Growth Curve, Hematological Parameters and Macrophage Function of Rats

“…According the National Research Council nutrient requirements of rats (36), the minimum protein requirement for adult rats is 9% and 12% for pregnant rats (nearly the content of casein utilized in our low protein diet). Different authors reported mild protein malnutrition, the reduction in the protein content in the diet from 25 to 8% casein, calorically compensated by carbohydrates, in a restricted period of life such as pregnancy or the lactating period (9,37,38). Rats fed such low protein diets adjust their food intake to a level just sufficient to maintain body weight and may represent a mechanism by which low-protein-fed rats partially compensate for their low protein intake (39).…”

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D3versus D2Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

“…Few ligands possessing a marked preference for ␣ 2C -versus ␣ 2A /␣ 2B -ARs have been described previously (Hieble et al, 1995), so S33138 may serve as a useful template for construction of chemically novel selective ␣ 2C -AR antagonists. Exploration of the significance of ␣ 2C -AR blockade to the functional profile of S33138 would be of interest because activation of ␣ 2C -ARs in frontal cortex and hippocampus may compromise cognitive performance (Marcus et al, 2005;Soto-Moyano et al, 2005). Moreover, antagonism of corticolimbic and striatal ␣ 2C -ARs may contribute to the atypical profile of clozapine, including its low EPS potential (Millan et al, 2001'02;Kalkman and Loetscher, 2003;Svensson, 2003).…”

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

“…In addition, these animals showed increased neocortical expression of the a 2C -adrenoceptor subtype during postnatal life (Sierralta et al, 2006;Soto-Moyano et al, 2005). Together with the altered profile in central noradrenergic systems, the neocortex of adult prenatally malnourished animals shows weakened electrophysiological indices, including decreased ability of callosal-cortical synapses to perform temporal summation (Soto-Moyano et al, 1998a) and to maintain long-term synaptic potentiation (Hernández et al, 2008;Soto-Moyano et al, 2005).…”

“…However, this insidious form of protein maternal malnutrition, the so-called ''hidden'' prenatal malnutrition (Resnick et al, 1982), results in altered noradrenergic function in the neocortex of the offspring, as revealed by increased concentration and release of cortical noradrenaline during early postnatal life, followed by decreased cortical release of the neurotransmitter during adulthood (Soto-Moyano et al, 1998a, 1998b. In addition, these animals showed increased neocortical expression of the a 2C -adrenoceptor subtype during postnatal life (Sierralta et al, 2006;Soto-Moyano et al, 2005). Together with the altered profile in central noradrenergic systems, the neocortex of adult prenatally malnourished animals shows weakened electrophysiological indices, including decreased ability of callosal-cortical synapses to perform temporal summation (Soto-Moyano et al, 1998a) and to maintain long-term synaptic potentiation (Hernández et al, 2008;Soto-Moyano et al, 2005).…”

“…It has been hypothesized that many of the deficits in functional plasticity observed in prenatally malnourished animals are due, at least in part, to the above mentioned modifications in brain noradrenergic systems (Soto-Moyano et al, 2005). In fact, central nervous system noradrenaline critically influences long-term potentiation (LTP) in cerebral cortex (Kobayashi, 2007;Komatsu, 1996;Marzo, Bai, & Otani, 2009;Nowicky, Christofi, & Bindman, 1992) and hippocampus (Bramham, Bacher-Svendsen, & Sarvey, 1997;Hopkins & Johnston, 1988;Marzo et al, 2009;O'Dell et al, 2010;Radisavljevic, Cepeda, Peacock, Buchwald, & Levine, 1994;Schimanski, Ali, Baker, & Nguyen, 2007;Swanson-Park et al, 1999) as well as memory formation (Crowe, Ng, & Gibbs, 1990;Gibbs, 1991;Sternberg, Korol, Novack, & McGaugh, 1986), through balanced activation of specific receptors.…”