FFAR1

Central nervous system

FFAR1 is expressed on the neurons and some other cell types in the olfactory bulb, striatum, hippocampus, midbrain, hypothalamus, cerebellum, cerebral cortex, and caudate nucleus of the brain as well as in the spinal cord. FFAR1-activating fatty acids, particularly docosahexaenoic acid, are thought to play critical roles in neurons by maintaining their surface membrane integrity, survival, synaptic functions (synapses are specialize parts of neurons which communicate with other neurons), ion channel functions (e.g. communication between cells), and in suppressing the development of certain central nervous system disorders. However, it is often not clear that docosahexaenoic acid achieves these effects by activating FFAR1. The following studies have implicated FFAR1 in various central nervous system functions and/or disorders. 1)Ffar1 gene knockout mice showed abnormally reduced anxiety-like behavior in anxiety-inducing tasks compared to control mice. 2)Ffar1 gene knockout female mice had abnormally low anxiety responses, abnormally low locomotor activity, and impaired maternal care behavior (i.e., higher rates of offspring neglect and infanticide) compared to control female mice. 3) Obese, diabetic male C57BL6/J mice and db/db obese, diabetic mice (an animal disease model) have fear-associated learning and memory impairments as determined in various behavioral tests; GW5908 and docosahexaenoic acid reduced these impairments and GW1100 blocked docosahexaenoic acid's effects on learning and memory. 4) GW9508 completely restored the learning and memory of mice that had impaired learning and memory due to scopolamine treatment. 5) GW9508 reduced the cognitive deficits in A-beta AD mice (i.e. a mouse model of Alzheimer's disease); this reduction was blocked by treating the mice with GW1100. 6) GW9508 similarly improved learning and memory in A-beta AD mice evaluated with other cognition tests. And 7) the highly selective FFAR1 agonist TAK-875 reduced the cognitive impairments that occur in APPswe/PS1dE9 mice (another model of Alzheimer disease). These results suggest that FFAR1 may be, and should be evaluated as, a potentile target for the treatment of brain developmental, emotional, and mental impairments such as Alzheimer's disease.