The Cross-Border Biotech Blog

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Friday Science Review: August 9, 2013

Cognitive decline, memory impairment, and anxiety are all typical parts of normal aging. New research published in the Journal of Neuroscience from the lab of Dr. Remi Quirion at McGill University sheds light on cellular mechanisms in the brain that may underlie this decline. Dynorphins, endogenous opioid-like proteins, appear to be increased in aged brains, and through activation of specific opioid receptors can decrease the function of synaptic connections releasing the amino acid neurotransmitter glutamate. Glutamate is the most common neurotransmitter in the brain and acts on several different receptor types, but the effect of dynorphin appears to arise through reduction in activity of a specific group of glutamate receptors, the metabotropic glutamate receptors (mGluRs). mGluRs can be important for different forms of synaptic plasticity, or the remodeling of neural connections, and appear to be important for decreasing the strength of certain synapses in order to properly shape neural circuits that underlie learning and memory formation. The hypothesis that Dr. Quirion’s group pursued was that increased dynorphin expression in aging brains leads to decreased mGluR activation which in turn limits the synaptic plasticity required for memory and other cognitive processes. To examine this, the group compared anatomical, physiological, and behavioral characteristics of wild-type mice and mice that had the dynorphin precursor, prodynorphin, knocked out. In general, young and middle-aged wild-type mice did not differ from young and middle-aged prodynorphin knockout mice. However, many differences were observed between old wild-type mice and old prodynorphin knockout mice. Old prodynorphin knockout mice had higher mGluR expression than old wild-type mice, and they exhibited mGluR-mediated plasticity at a level similar to young and middle-aged mice. Additionally, on behavioral tests of memory, learning, and anxiety, the prodynorphin knockout mice performed better than and displayed less anxiety behaviors than old wild-type mice. In fact, old prodynorphin knockout mice performed similarly to young and middle-aged mice on the behavioral tasks. To confirm that these changes were mediated by mGluRs and dynorphin receptors, the authors also performed behavioral tests in mice that had received pharmacological treatment. In old wild-type mice, pharmacologically increasing the activity of mGluRs or blocking the activity of dynorphin receptors resulted in greatly improved performance on the memory and learning tasks and in decreased anxiety behaviors. Conversely, in old prodynorphin knockout mice pharmacologically inhibiting the activity of mGluRs resulted in poorer performance on memory tasks and in increased anxiety behaviors. Together, these data clearly demonstrate that increases in dynorphin during normal mammalian aging can cause a reduction in mGluR-mediated synaptic changes that underlie learning, memory, and anxiety, and they identify a pathway that can be targeted to improve cognitive ability in the aging population.

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