In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model.
In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spin-spin (T(2)) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75(NTR) and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre- and postsynaptic profiles in these target areas. T(2) effects were negligible in Ts1Cje mice that are diploid for App and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimer's disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations.
Chen
Yuanxin
Y
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, United States.
Dyakin
Victor V
VV
Branch
Craig A
CA
Ardekani
Babak
B
Yang
Dunsheng
D
Guilfoyle
David N
DN
Peterson
Jesse
J
Peterhoff
Corrinne
C
Ginsberg
Stephen D
SD
Cataldo
Anne M
AM
Nixon
Ralph A
RA
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004525:Efferent Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018628:Gene Dosage / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D011237:Predictive Value of Tests; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D012680:Sensitivity and Specificity; D012686:Septal Nuclei / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D014314:Trisomy / Q000235:genetics
D020800:Receptor, Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA; D000109:Acetylcholine