Alterations of markers related to synaptic function in aging rat brain, in normal conditions or under conditions of long-term dietary manipulation

Abstract

Neurochemical alterations of markers related to synaptic function are potential candidates for age-related impairment of brain function and cognition. The process of aging, including brain aging, can be counteracted to some degree by maintaning animals in long-term conditions of caloric restriction, or supplementing their diet with antioxidant substances. We report here that the age-related decline of the cholinergic and GABAergic systems, that takes place in some CNS regions of aged rats, is not affected by maintaining them under conditions of dietary restriction and, therefore, of reduced calorie intake, from the 12th to the 30th month of age. We also notice the same lack of effect by adding, during the same period, the aging rat diet with the potential antioxidant substance, N-acetylcysteine (NAC). The same dietary manipulations are also unable to counteract the derangement of the first step of the main biosynthetic pathway for polyamines, putative neuromodulators in the CNS, that occurs in the aged spinal cord. Some age-related alterations in the expression of different subunits of the NMDA-type glutamate receptors in some CNS regions of aged rats were instead, at least in some cases, counteracted by long-term dietary manipulation.

Introduction

Normal brain aging is accompanied by behavioral alterations and in particular by impairment of learning and memory (Ingram et al., 1994, Strong, 1998). Surprisingly, alterations of several structural and functional parameters are relatively small during normal brain aging (Morrison and Hof, 1997, Mrak et al., 1997). Modification of neurochemical markers, in particular those linked to the synaptic function, have been considered obvious candidates for age-related behavioral and cognitive impairment (Ingram et al., 1981, Bartus et al., 1982, Strong et al., 1982, Colombo and Gallagher, 1998). We have recently performed a study surveying the topographical alterations of several neurotransmitter-related markers in brain regions of young adult (4-month-old) and aged (30-month-old) rats (Virgili et al., 2001a). From this study, cholinergic and GABAergic systems appeared moderately compromised in several brain regions and in the spinal cord, specific markers for these neurotransmitters showing significant decreases ranging from 15 to 30% in aged rats (Virgili et al., 2001a). Using the same groups of animals, we also demonstrated that, restricted to the spinal cord of the aged rats, a dramatic derangement of polyamine metabolism did occur in the aged rats (Virgili et al., 2001b).

The aging process is effectively counteracted by dietary restriction, and by the consequent decrease of caloric intake, in several animal species and the age-related compromission of brain function might be, at least in part, relieved under these conditions (Prolla and Mattson, 2001, Mattson et al., 2003). In mammals, dietary restriction counteracts the age-related induction of stress and inflammatory response genes (Lee et al., 2000), enhances neurotrophin expression and adult neurogenesis in the hippocampus (Lee et al., 2002) and increases the expression of an apoptosis suppressor in aging brain (Shelke and Leeuwenburgh, 2003). One of the ways by which dietary restriction might improve brain aging bas been related to decrease of oxidative stress, as accumulation of free oxygen radicals is considered an important adverse factor in aging and in neurodegenerative processes and antioxidant treatments may be beneficial against age-related disfunctions (O’Donnel and Lynch, 1998, Contestabile, 2001; Prolla and Mattson, 2001; Golden et al., 2002).

With the experiments reported here, we have attempted to counteract previously described alterations of a cholinergic and a GABAergic marker (Virgili et al., 2001a) in several brain regions of 30-month-old rats, through long-term (18 months) dietary restriction or dietary supplementation with a glutathion precursor with potential antioxidant properties, N-acetylcysteine (NAC). In the spinal cord of the same rats, we have also studied whether the same treatment counteracted the previously described increase in activity of the key enzyme for polyamine metabolism, ornithine decarboxylase (ODC) (Virgili et al., 2001b). Finally, we have made new observations on the age-related altered expression of the main subunits of the ionotropic NMDA and non-NMDA glutamate receptors and we have tested the effect of long-term dietary manipulation on them.