Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome.
Down syndrome (DS) is a neurological disorder causing impaired learning and memory. Partial trisomy 16 mice (Ts65Dn) are a genetic model for DS. Previously, we demonstrated widespread alterations of pre- and postsynaptic elements and physiological abnormalities in Ts65Dn mice. The average diameter of presynaptic boutons and spines in the neocortex and hippocampus was enlarged. Failed induction of long-term potentiation (LTP) due to excessive inhibition was observed. In this paper we investigate the morphological substrate for excessive inhibition in Ts65Dn. We used electron microscopy (EM) to characterize synapses, confocal microscopy to analyze colocalization of the general marker for synaptic vesicle protein with specific protein markers for inhibitory and excitatory synapses, and densitometry to characterize the distribution of the receptor and several proteins essential for synaptic clustering of neurotransmitter receptors. EM analysis of synapses in the Ts65Dn vs. 2N showed that synaptic opposition lengths were significantly greater for symmetric synapses (approximately 18%), but not for asymmetric ones. Overall, a significant increase in colocalization coefficients of glutamic acid decarboxylase (GAD)65/p38 immunoreactivity (IR) (approximately 27%) and vesicular GABA transporter (VGAT)/p38 IR (approximately 41%) was found, but not in vesicular glutamate transporter 1 (VGLUT1)/p38 IR. A significant overall decrease of IR in the hippocampus of Ts65Dn mice compared with 2N mice for glutamate receptor 2 (GluR2; approximately 13%) and anti-gamma-aminobutyric acid (GABA)(A) receptor beta2/3 subunit (approximately 20%) was also found. The study of proteins essential for synaptic clustering of receptors revealed a significant increase in puncta size for neuroligin 2 (approximately 13%) and GABA(A) receptor-associated protein (GABARAP; approximately 13%), but not for neuroligin 1 and gephyrin. The results demonstrate a significant alteration of inhibitory synapses in the fascia dentata of Ts65Dn mice.
Belichenko
Pavel V
PV
Department of Neurology & Neurological Sciences, the Center for Research and Treatment of Down Syndrome and Neuroscience Institute at Stanford University, Stanford, California 94305-5489, USA. pavel_belichenko@yahoo.com
Kleschevnikov
Alexander M
AM
Masliah
Eliezer
E
Wu
Chengbiao
C
Takimoto-Kimura
Ryoko
R
Salehi
Ahmad
A
Mobley
William C
WC
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D017729:Presynaptic Terminals / Q000473:pathology / Q000648:ultrastructure*; D018079:Receptors, GABA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000648:ultrastructure*; D016708:Synaptophysin / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D011993:Recombinant Fusion Proteins; C493465:Slc17a7 protein, mouse; D016708:Synaptophysin; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C073441:gephyrin; C093438:neuroligin 1; C098003:neuroligin 2; D005968:Glutamate Decarboxylase