The ε4 allele of apolipoprotein E (apoE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD) and is also implicated in cognitive deficits associated with normal aging. The biological mechanisms by which APOE genotype affects cognitive processes or AD pathogenesis remain unclear, but interactions of apoE with amyloid β peptide (Aβ) are thought to play an important role in mediating apoE's isoformspecific effects on brain function. Here, we investigated the potential isoform-dependent effects of apoE on behavioral and cognitive performance in human apoE3 and apoE4 targeted-replacement (TR) mice that also overexpress the human amyloid precursor protein (APP). Beginning at 6-7 months of age, female APP-Yac/apoE3-TR ('apoE3') and APP-Yac/apoE4-TR ('apoE4') mice were tested on a battery of tests to evaluate basic sensorimotor functioning, spatial working memory, spatial recognition, episodic-like memory and attentional processing. Compared with apoE3 mice, a generalized reduction in locomotor activity was observed in apoE4 mice. Moderate, but significant, cognitive impairments were also detected in apoE4 mice in the novel object-location preference task, the contextual fear conditioning test, and a two-choice visual discrimination/detection test, however spontaneous alternation performance in the Y-maze was spared. These results offer additional support for the negative impact of apoE4 on both memory and attention and further suggest that APP-Yac/apoE-TR mice provide a novel and useful model for investigating the role of apoE in mediating susceptibility to cognitive decline.

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In addition to its role in neuronal migration during embryonic development, doublecortin (DCX) plays a role in hippocampal neurogenesis across the lifespan. Hippocampal neurons exhibit a high degree of synaptic plasticity while they are in the DCX phase. While previous studies have reported that behavioral training on hippocampus-dependent tasks can enhance neuron survival, little was known about the stage of development of those neurons and, particularly, whether a large pool of the surviving new neurons remains in the DCX phase for a prolonged period after training. Here we report that spatial navigation training increases the pool of neurons that are in the DCX phase four weeks after training ended. Thus, the stock of DCX-expressing neurons in the hippocampus is affected by whether a hippocampus-dependent task has been encountered during the preceding few weeks.

Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.