TY  - JOUR
AU  - de Souza Silva, Maria A
AU  - Lenz, Bernd
AU  - Rotter, Andrea
AU  - Biermann, Teresa
AU  - Peters, Oliver
AU  - Ramirez, Alfredo
AU  - Jessen, Frank
AU  - Maier, Wolfgang
AU  - Hüll, Michael
AU  - Schröder, Johannes
AU  - Frölich, Lutz
AU  - Teipel, Stefan
AU  - Gruber, Oliver
AU  - Kornhuber, Johannes
AU  - Huston, Joseph P
AU  - Müller, Christian P
AU  - Schäble, Sandra
TI  - Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 110
IS  - 37
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2020-03360
SP  - 15097-15102
PY  - 2013
AB  - Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.
KW  - Acetylcholine: physiology
KW  - Aged
KW  - Aged, 80 and over
KW  - Aging: genetics
KW  - Aging: physiology
KW  - Aging: psychology
KW  - Animals
KW  - Cognition Disorders: genetics
KW  - Cognition Disorders: physiopathology
KW  - Cognition Disorders: psychology
KW  - Cognitive Dysfunction: genetics
KW  - Cognitive Dysfunction: physiopathology
KW  - Cognitive Dysfunction: psychology
KW  - Dementia: genetics
KW  - Dementia: physiopathology
KW  - Dementia: psychology
KW  - Female
KW  - Genetic Association Studies
KW  - Humans
KW  - Learning: drug effects
KW  - Learning: physiology
KW  - Male
KW  - Maze Learning: drug effects
KW  - Maze Learning: physiology
KW  - Memory: drug effects
KW  - Memory: physiology
KW  - Middle Aged
KW  - Models, Animal
KW  - Models, Neurological
KW  - Polymorphism, Single Nucleotide
KW  - RNA, Messenger: genetics
KW  - RNA, Messenger: metabolism
KW  - Rats
KW  - Rats, Wistar
KW  - Receptors, Neurokinin-3: agonists
KW  - Receptors, Neurokinin-3: genetics
KW  - Receptors, Neurokinin-3: physiology
KW  - RNA, Messenger (NLM Chemicals)
KW  - Receptors, Neurokinin-3 (NLM Chemicals)
KW  - Acetylcholine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23983264
C2  - pmc:PMC3773732
DO  - DOI:10.1073/pnas.1306884110
UR  - https://pub.dzne.de/record/137038
ER  -