title: Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.
abstract: Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, 53127 Bonn, Germany.
authors.forename: Onder
authors.initials: O
authors.lastname: Albayram
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
authors.forename: Julika
authors.initials: J
authors.lastname: Pitsch
authors.forename: Anastasia
authors.initials: A
authors.lastname: Piyanova
authors.forename: Kim
authors.initials: K
authors.lastname: Neitzert
authors.forename: Karola
authors.initials: K
authors.lastname: Poppensieker
authors.forename: Daniela
authors.initials: D
authors.lastname: Mauer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Michel
authors.forename: Anne
authors.initials: A
authors.lastname: Legler
authors.forename: Albert
authors.initials: A
authors.lastname: Becker
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Andras
authors.initials: A
authors.lastname: Bilkei-Gorzo
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000502:physiology*; D002452:Cell Count; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000473:pathology / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D015850:Interleukin-6; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid