Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N-methyl-D-aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stressinduced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.glutamate transporter ͉ interference peptide ͉ synaptic plasticity ͉ water maze ͉ corticosterone C ognitive functions such as learning and memory are greatly affected by stress. Memory retrieval in humans is especially vulnerable to acute psychological stress (1) or cortisol treatment (2), effects caused in part by alterations in medial temporal lobe function (3). In rodents, acute stress or administration of glucocorticoids disrupts the retrieval of hippocampal-dependent spatial memory (4). Furthermore, stress and glucocorticoids have a profound influence on the physiology of the hippocampal CA1 region by inhibiting long-term potentiation (LTP) (5-7) and enabling long-term depression (LTD) (7,8), the two most well characterized forms of synaptic plasticity and proposed cellular substrates for learning and memory (9, 10). However, it remains to be established whether the alterations in either LTP or LTD caused by stress contribute to the stress-induced impairment of spatial memory retrieval.Considerable experimental evidence supports the role of hippocampal LTP in spatial memory (11)(12)(13)(14), and theoretical accounts of associative memory, based on neural network models, suggest that a balance between LTP and LTD may underlie efficient memory storage (10, 15). By using two recently developed specific inhibitors of LTD (16, 17), the present experiments assess the role of LTD in the spatial memory retrieval deficits induced by acute stress and provide strong evidence for a role of hippocampal LTD in mediating this aspect of acute stress-induced impairment of cognitive function in adult rats. ResultsBlocking the Induction of LTD Prevents the Stress-Induced Impairment of Spatial Memory Retrieval. It is well accepted that the induction of hippocampal CA1 homosynaptic LTD depends on the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) (10), which are heteromeric complexes of NR1 subunits and at least one type of NR2 subunit (NR2A-D) (18). Converging evidence supports the hypothesis that the subunit composition of NMDARs may c...

Digital technology is transforming the development of drugs for Alzheimer's disease and was the topic of the Alzheimer's Association's Research Roundtable on its May 23–24, 2017 meeting. Research indicates that wearable devices and unobtrusive passive sensors that enable the collection of frequent or continuous, objective, and multidimensional data during daily activities may capture subtle changes in cognition and functional capacity long before the onset of dementia. The potential to exploit these technologies to improve clinical trials as both recruitment and retention tools as well as for potential end points was discussed. The implications for the collection and use of large amounts of data, lessons learned from other related disease areas, ethical concerns raised by these new technologies, and regulatory issues were also covered in the meeting. Finally, the challenges and opportunities of these new technologies for future use were discussed.