Effects of leptin on memory processing

Abstract

Leptin is a peptide hormone secreted by adipose tissue. Studies have shown that leptin crosses the blood–brain barrier (BBB) by a saturable transport system where it acts within the hypothalamus to regulate food intake and energy expenditure. Leptin also acts in the hippocampus where it facilitates the induction of long-term potentiation and enhances NMDA receptor-mediated transmission. This suggests that leptin plays a role in learning and memory. Obese mice and rats, which have leptin receptor deficiency, have impaired spatial learning. In disease states such as diabetes, humans and animals develop leptin resistance at the BBB. This suggests that low leptin levels in the brain may be involved in cognitive deficits associated with diabetes. In the current study, the effects of leptin on post-training memory processing in CD-1 mice were examined. Mice were trained in T-maze footshock avoidance and step down inhibitory avoidance. Immediately after training, mice received bilateral injections of leptin into the hippocampus. Retention was tested 1 week later in the T-maze and 1 day later in step down inhibitory avoidance. Leptin administration improved retention of T-maze footshock avoidance and step down inhibitory avoidance. Leptin administered 24 h after T-maze training did not improve retention when tested 1 week after training. SAMP8 mice at 12 months of age have elevated amyloid-beta protein and impaired learning and memory. We examined the effect of leptin on memory processing in the hippocampus of 4 and 12 months old SAMP8 mice. Leptin improved retention in both 4 and 12 months old SAMP8 mice; 12 month SAMP8 mice required a lower dose to improve memory compared to 4 months SAMP8 mice. The current results indicate that leptin in the hippocampus is involved in memory processing and suggests that low levels of leptin may be involved in cognitive deficits seen in disease states where leptin transport into the CNS is compromised.

Introduction

Leptin is a peptide hormone involved in modulation of food intake and energy balance [2], [3], [5], [6], [20]. These actions are thought to occur through the leptin receptors mainly in the hypothalamic nuclei. However, leptin receptors exist throughout the brain including the hippocampus, an area of the brain involved in learning and memory [14]. Leptin has been found to facilitate long-term potentiation in the hippocampus, a process important for memory processing [31], [35]. The facilitation of synaptic plasticity occurs via enhanced NMDA receptor-mediated Ca²⁺ influx. Leptin receptor deficient rodents have impaired spatial memory, a process that relies heavily on the hippocampus [21]. This has lead to the suggestion that low levels of leptin in the brain may be related to impaired memory found in disease states such as diabetes where leptin transport into the brain is impaired.

Leptin modulates hypothalamic feeding circuits [16]. In normal weight humans and animals leptin serves to signal the brain to stop eating [3], [23]. The hypothalamus, the primary regulator of energy expenditure, is comprised of two populations of neurons: the orexigenic (appetite-stimulating) neurones containing neuropeptide Y (NPY) and agouti-related protein (AGRP), and the anorexigenic (appetite-suppressing) neurones, which produce the neuropeptides pro-opiomelanocortin (POMC) and cocaine-and-amphetamine-regulated transcript (CART). Both groups of neurones express leptin receptors, but are differentially effected by the hormone. Leptin increases the expression of POMC mRNA while decreasing the expression of mRNA encoding for NPY [30], [32]. Similarly, leptin is thought to counteract the effects of the orexigenic peptide ghrelin and attenuate adiponectin and insulin levels [34]. Deficiencies in leptin result in obesity [4], [36].

Leptin works outside the hypothalamus. Patients with both schizophrenia and depression with normal body mass indices have low leptin levels [18]. This occurs even if the patient is being treated with psychotropic medication suggesting a need to examine leptin in these psychiatric conditions. Evidence also exists for a role of leptin in brain development. Studies of ob/ob mice, which are leptin-deficient, find that their brains are smaller in both weight and cortical volume [33]. Administration of leptin for 2 weeks in 4-week-old mice resulted in a 10% increase in brain weight and a 19% increase in total brain DNA indicating that leptin increases cell numbers.

Diseases of aging are another state where changes in leptin are starting to be considered an important factor. Circulating leptin has been found to be lower in patients with Alzheimer's disease and vascular dementia with anorexia [29]. In addition, leptin has been found to decrease amyloid-beta load in transgenic mice with elevated Aβ [10]. Together these findings suggest that decreased leptin, perhaps due to neuroendocrine dysfunction, may be associated with elevated Aβ and dementia. The SAMP8 mice are a strain of mice with elevated amyloid-beta protein (Aβ) and learning and memory impairments by 12 months of age [13], [19], [24], [25], [26]. Aβ protein is considered to be a major contributor to the dementia of Alzheimer's disease (AD). In SAMP8 mice, administration of Aβ antibody or antisense directed at the Aβ region of the APP peptide reverses the memory impairment seen in 12 months SAMP8 mice. In addition, SAMP8 mice have a decreased sensitivity to memory-enhancing compounds such as arecoline, a cholinergic agonist, and glutamate when injected into the hippocampus. The decreased sensitivity can be reversed when Aβ antibody is given 24 h prior to training and drug administration [24]. Recent studies have suggested that administration of leptin significantly reduced Aβ levels in transgenic mice, which overexpress Aβ [10].

The purpose of the current studies is to examine the effect of leptin on memory processing in the hippocampus in both normal outbred CD-1 mice and in SAMP8 mice, which developed elevated amyloid-beta and memory deficits with advancing age.