Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. Syngap1 encodes a synaptic RasGAP (SynGAP) that is largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling pathways linked to NMDA receptor (NMDAR)-mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion. Syngap1 has alternative transcriptional start sites and several alternatively spliced C-terminal exons that result in many possible SynGAP isoforms. Human SYNGAP1 haploinsufficiency results from a truncation of the full-length protein. Exon 7 contains the first common methionine present in the shortest splice variant.

The SYNGAP1^lx-st allele has a loxP-flanked neo-STOP cassette upstream of exon 6 of the Syngap1 gene. Following cre-mediated recombination that removes the floxed region, SynGAP expression and function are fully recovered.

Prior to Cre recombinase exposure, mice heterozygous for the SYNGAP1^lx-st allele express a SynGAP protein truncated after exon 5 (known to be an inactivate SynGAP protein), as well as diminished levels of functional SynGAP (from the wildtype allele). Therefore, the phenotype of heterozygotes (SYNGAP1^lx-st/+) is the same as mice heterozygous for the global knockout allele, and both are a model of human SYNGAP1 haploinsufficiency - exhibiting normal synaptic transmission, modest defects in synaptic plasticity, enhanced synaptic function (accelerated rate of glutamatergic synapse maturation) during early neural development and profound cognitive and behavioral abnormalities. Specifically, heterozygous SynGAP-deficiency significantly disrupts excitatory/inhibitory (E/I) balance in the neural networks that support cognition and behavior. Abnormal behavioral phenotypes can be observing as early as 21 days of age with ~100% penetrance (although physiological abnormalities can be measured even earlier through other methods such as electrophysiological recordings). Furthermore, homozygotes (SYNGAP1^lx-st/lx-st are phenotypically the same as global knockout homozygotes - exhibiting complete postnatal lethality between 2-5 days of age.

When SYNGAP1^lx-st are bred to mice that express Cre recombinase, the resulting offspring may be useful in generating tissue-specific restoration of full-length SynGAP expression. For example, when SYNGAP1^lx-st/+ mice are bred hemizygous for the CAGGCre-ER^TM transgene (Stock No. 004682), the resulting animals allow widespread, tamoxifen-inducible SynGAP restoration. In those mice, complete restoration of SynGAP protein expression in adults had no detectable benefit on behavior or cognition - demonstrating that SYNGAP1 haploinsufficiency is a disorder of brain development.