Neurosteroids: Deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus

Abstract

Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22-24 month-old) male Sprague-Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a ␥-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and͞or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and͞or treatment of age-related memory disorders.

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

“…Inhibition of de novo synthesis of neurosteroids reduced dendritic spine formation in Purkinje cells in organotypic slice cultures (Sakamoto et al, 2002) and remyelination of damaged nerves by Schwann cells (Koenig et al, 1995). In addition, low hippocampal levels of pregnenolone sulfate correlate with poor performance in memory tasks by rodents (Vallee et al, 1997). Administration of neurosteroids has been proposed as a therapeutic treatment for various pathologies such as seizure disorders and memory loss attributable to aging (Akwa et al, 2001; for review, see Mellon and Griffin, 2002).…”

“…Alterations in levels of locally produced neurosteroids in the hypothalamus, hippocampus, and other regions may serve as crucial paracrine modulators of essential brain functions, including sexual drive, learning, and memory (Majewska et al, 1986;Genazzani et al, 1995;Frye et al, 1996;Calogero et al, 1998;Akwa et al, 2001). Deficits in neurosteroid production may contribute to a variety of disorders, including dementia, epilepsy, premenstrual syndrome, and postpartum depression (Vallee et al, 1997;Smith et al, 1998;Beyenburg et al, 1999). Consequently, it is critical that we understand the mechanism of neurosteroid biosynthesis and regulation.…”

The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: Distinct mechanisms?

“…Among them, the neurosteroid pregnenolone sulfate (3␤-hydroxy-5-pregnen-20-one sulfate, PREGS) has been well described as a potent steroidal enhancer of learning and memory processes in rodents (1)(2)(3)(4)(5)(6). Of particular interest is the physiological role of PREGS in the hippocampus, which was recently demonstrated for the preservation of age-related spatial memory loss (4).…”

Characterization of the convulsant action of pregnenolone sulfate

“…Finally, it is possible that PS preferentially affects the hippocampus. Studies on the effect of PS on learning and memory suggested that limbic structures are particular targets of action of PS (Flood et al, 1995;Vallee et al, 1997).…”

“…Hippocampus was chosen as the site for PS infusion for several reasons. PS is present in high concentrations in the hippocampus (Wang et al, 1997) and can modulate learning and memory function when infused into this structure (Flood et al, 1995;Vallee et al, 1997). Moreover, the hippocampus has long been implicated in temporal lobe epilepsy and is the focus for investigation into the basic mechanisms of epileptogenesis (McNamara, 1999).…”