title: Altered thalamocortical development in the SAP102 knockout model of intellectual disability.
abstract: Genetic mutations known to cause intellectual disabilities (IDs) are concentrated in specific sets of genes including both those encoding synaptic proteins and those expressed during early development. We have characterized the effect of genetic deletion of Dlg3, an ID-related gene encoding the synaptic NMDA-receptor interacting protein synapse-associated protein 102 (SAP102), on development of the mouse somatosensory cortex. SAP102 is the main representative of the PSD-95 family of postsynaptic MAGUK proteins during early development and is proposed to play a role in stabilizing receptors at immature synapses. Genetic deletion of SAP102 caused a reduction in the total number of thalamocortical (TC) axons innervating the somatosensory cortex, but did not affect the segregation of barrels. On a synaptic level SAP102 knockout mice display a transient speeding of NMDA receptor kinetics during the critical period for TC plasticity, despite no reduction in GluN2B-mediated component of synaptic transmission. These data indicated an interesting dissociation between receptor kinetics and NMDA subunit expression. Following the critical period NMDA receptor function was unaffected by loss of SAP102 but there was a reduction in the divergence of TC connectivity. These data suggest that changes in synaptic function early in development caused by mutations in SAP102 result in changes in network connectivity later in life.
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Crocker-Buque
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Currie
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Liliana L
authors.initials: LL
authors.lastname: Luz
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
authors.forename: Seth G
authors.initials: SG
authors.lastname: Grant
authors.affiliation: Department of Psychology and Neuroscience, Dalhousie University, 1355 Oxford Street, Halifax, NS B3H 4R2, Canada.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Duffy
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK mdaw@staffmail.ed.ac.uk p.kind@ed.ac.uk.|Centre for Brain Development and Repair, InStem, Bangalore 560065, India.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.affiliation: Centre for Integrative Physiology and Patrick Wild Centre, University of Edinburgh, Edinburgh EH8 9XD, UK mdaw@staffmail.ed.ac.uk p.kind@ed.ac.uk.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Daw
mesh_terms: D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D051528:Guanylate Kinases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D017384:Sequence Deletion; D013003:Somatosensory Cortex / Q000254:growth & development* / Q000473:pathology; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases