SAPAP family proteins were originally identified as postsynaptic density (PSD) components that interact with the PSD95 and Shank families of proteins12-13
, two other multi-domain postsynaptic scaffolding proteins at excitatory synapses. Together, these three groups of proteins are thought to form a key scaffolding complex that regulates the trafficking and targeting of neurotransmitter receptors and signaling molecules to the postsynaptic membrane of excitatory synapses14-16
. There are four highly homologous genes in the SAPAP family13
. Of these, SAPAP1, 3, and 4 are highly, but differentially, expressed in several regions of the brain17,18
. Notably, SAPAP3 is the only member highly expressed in the striatum. To facilitate study of the in vivo
function of SAPAP proteins at synapses, we generated knockout mice for the SAPAP3 gene using homologous recombination in mouse ES cells (Supplementary Fig. S1a-d
). Mice homozygous for SAPAP3 deletion (SAPAP3-/-
) were born at the expected Mendelian rate, grew to adulthood with body weights similar to wildtype mice, and were fertile. Anatomical and histological analyses of brain showed that SAPAP3-/-
mice were grossly normal (data not shown).
By the age of 4-6 months, however, SAPAP3-/- mice developed lesions on their head, neck, and snout regions (). This phenotype was 100% penetrant. Lesions were usually first noticed as a patch of hairless skin under the eyes or swelling of the snout, progressing to relatively symmetric bilateral lesions encompassing large parts of the neck and head. SAPAP3-/- mice developed lesions regardless of whether they were housed alone or with cagemates. Lesions were not observed on wildtype or heterozygous mice even when housed in the same cage with SAPAP3-/- mice from birth, thereby excluding the possibility that lesions were caused by allogrooming or were the result of aggressive encounters with other SAPAP3-/- mice. In fact, SAPAP3-/- mice were not observed to behave aggressively, but were often seen engaged in self-grooming whether they were housed alone or in groups.
Facial lesions, excessive grooming and anxiety-like behaviors in SAPAP3 mutant mice
Given the obvious lesions on the SAPAP3-/-
mice, we tested the possibility that their lesions might be caused by peripheral cutaneous defects, such as inflammation or abnormal afferent sensation. We examined facial skin from pre-lesion SAPAP3-/-
mice that exhibited increased grooming. Histological analysis of skin did not reveal any anatomical differences among wildtype, SAPAP3+/-
mice, and no lymphocytic or granulocytic infiltration was observed (Supplementary Fig. S1e, f
). We did, however, find lymphocytic/granulocytic infiltration in skin with lesions, likely due to injury and infection (Supplementary Fig. S1g
). No differences were detected in sensory innervation among wildtype, SAPAP3+/-
mice; hair-nerve end organs, lobular corpuscle-like nerve endings, and free epidermal nerve endings were present and not different between SAPAP3-/-
and control mice (Supplementary Fig. S1h, i
). Thus, our examination revealed no obvious peripheral defects that would suggest a cause for the lesions. Together, these findings raised the possibility that SAPAP3-/-
mice have excessive and injurious self-grooming behavior.