Age-Related Cognitive Impairment: Role of Reduced Synaptobrevin-2 Levels in Deficits of Memory and Synaptic Plasticity

Abstract

Cognitive impairment in the aging population is quickly becoming a health care priority, for which currently no disease-modifying treatment is available. Multiple domains of cognition decline with age even in the absence of neurodegenerative diseases. The cellular and molecular changes leading to cognitive decline with age remain elusive. Synaptobrevin-2 (Syb2), the major vesicular SNAP receptor protein, highly expressed in the cerebral cortex and hippocampus, is essential for synaptic transmission. We have analyzed Syb2 protein levels in mice and found a decrease with age. To investigate the functional consequences of lower Syb2 expression, we have used adult Syb2 heterozygous mice (Syb2) with reduced Syb2 levels. This allowed us to mimic the age-related decrease of Syb2 in the brain in order to selectively test its effects on learning and memory. Our results show that Syb2 animals have impaired learning and memory skills and they perform worse with age in the radial arm water maze assay. Syb2 hippocampal neurons have reduced synaptic plasticity with reduced release probability and impaired long-term potentiation in the CA1 region. Syb2 neurons also have lower vesicular release rates when compared to WT controls. These results indicate that reduced Syb2 expression with age is sufficient to cause cognitive impairment.