Proceedings of The Physiological Society

Physiology 2012 (Edinburgh) (2012) Proc Physiol Soc 27, C63

Oral Communications

Mutant mice lacking Synapse Associated Protein 102 (SAP102) display defects in thalamocortical axon development and dendritic spine frequency

A. Crocker-buque1,2, S. Till1,2, A. Duszkiewicz1, C. Lowe1, P. C. Kind1,2

1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Midlothian, United Kingdom. 2. The Patrick Wild Centre for research into Autism, Fragile X Syndrome and Intellectual Disabilities, University of Edinburgh, Edinburgh, Midlothian, United Kingdom.


Mutations in the SAP102 gene, which encodes SAP102 have been found in families with a history of X-linked mental retardation (1). SAP102 is a member of the membrane associated guanylate kinase (MAGUK) family of synaptic scaffolding molecules that link NMDA receptors to downstream signalling targets in the post-synaptic density. MAGUKs are hypothesised to create microdomains of intracellular signalling pathways through mediating protein-protein interactions. SAP-102 directly binds to both the GluN2 subunit of the NMDA receptor and SynGAP, a synaptic Ras-GTPase activating protein (3). Genetic disruption of either cortical NMDA receptors (2) or SynGAP display cortical defects in early postnatal development (2). Therefore, we tested the hypothesis that SAP102 regulates early patterning of, and neuronal connectivity within, the mouse somatosensory cortex (S1) using a mouse model with a genetic deletion of the Sap102 gene. Sap102 -/y mice and their littermate controls were anaesthetised with a lethal dose (0.025 ml/g, I.P.) sodium pentobarbital and perfused transcardially. The brain was removed and sectioned for immunohistochemistry, Golgi-Cox staining method or carbocyanine dye (DiI) labelling. All data are represented as means ± S.E.M. and analysed using a two-tailed t test. Sap102 -/y show a reduction in body and brain mass throughout postnatal development, however laminar thickness of S1 is unchanged. Cortical map formation in Sap102 -/y mice is grossly normal although thalmocortical axon (TCA) patch size is reduced. This reduction in TCA patch size is cannot be explained by a reduction in total brain size, as this defect is significant when normalised to neocortical area (Sap102+/y 0.0052±0.00057, SAP102 -/y 0.0036±0.00036, n=9,6 respectively, p<0.05). DiI labelling reveals an increase in mediolateral extent of TCA branching indicating that the decrease in TCA patch size is not the result of reduced TCA length. Synapse formation was investigated in Sap102 -/y mice by comparing the distribution of dendritic spines in different cell types. We find the loss of SAP102 causes cell-type specific defects on the density of dendritic spines in the S1. On layer IV stellate cells dendritic spine density was increased in Sap102-/y mice compared to controls (Sap102+/y 8.52±0.46, SAP102 -/y 10.13±0.33, n=5, p<0.05) whereas spine density was decreased on the apical shaft of layer V pyramidal cells as they pass through layer IV (Sap102+/y 6.02±0.76, Sap102 -/y 8.36±0.54, n=12,11 respectively, p<0.05). Together these data indicate that SAP102 plays a key role during cortical development in the mouse, a time that corresponds to embryonic development in humans. Furthermore, the loss of SAP102 results in cell specific phenotypes in layer IV suggesting heterogeneous roles for the protein during cortical development.

Where applicable, experiments conform with Society ethical requirements