NRSF/REST Deficiency Impairs Cognitive Abilities in Aged Mice But Does Not Interfere with Memory Deficits of APP/PS1 Transgenic Mice

Abstract

NRSF/REST plays an important role in the neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST has been linked to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease-related memory deficits remain unclear. In this study, we conditionally deleted NRSF/REST in the dorsal telencephalon or neurons of wild-type and APP/PS1 transgenic mice, and evaluated their cognitive abilities at different ages. The data indicated that conditional NRSF/REST-deficient mice had an age-dependently diminished retrieval performance in a variety of memory tests and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. In addition, the NRSF/REST deficient mice were characterized by an increase of activated glial cells, complement C3 protein, and the transcription factor C/EBPβ in the cortex and hippocampus. However, reduction of NRSF/REST in APP/PS1 mice by conditional depletion did not worsen the Aβ load and memory performance. The experiments suggest an important role of NRSF/REST for the maintenance of memory and synaptic plasticity in ageing mice, and point toward its potential roles in the onset of ageing-related memory impairments. Conditional NRSF/REST knockout mice of this study could be reliable experimental models of non-Alzheimer dementia.