PSD95-SMASh mice have the SMASh cassette replacing the endogenous STOP codon of the discs large MAGUK scaffold protein 4 (Dlg4) gene, also known as PSD95. PSD95 is a postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity, and is broadly expressed in neurons of the cortex, hippocampus, and striatum. Specifically, the SMASh (Small Molecule-Assisted Shutoff) cassette contains a cis-cleaving hepatitis C virus (HCV) NS3 protease. The non-virulent NS3 protease will become active after translation and will self-cleave, leaving PSD95 protein intact. However, when an NS3 inhibitor drug such as asunaprevir (ASV) is applied, the fusion protein will not undergo cleavage, allowing for the degradation of the newly synthesized PSD95-SMASh-tagged fusion protein. Thus, copies of PSD95 synthesized during time of drug presence are selectively degraded. The donating investigator reports that homozygous and heterozygous mice are viable and fertile. This strain is useful for reversible posttranslational temporally-restricted shut off new PSD95 expression within a drug-specified window and to study the contribution of newly synthesized synaptic proteins to plasticity and memory. Of note, PSD95-TimeSTAMP2 mice (Stock No. <a href="https://www.jax.org/strain/038073">038073</a>) contain a Cre-inducible TimeSTAMP (Time-Specific Tagging for the Age Measurement of Proteins) cassette which is useful for visualizing newly synthesized PSD95 where preservation of normal neuronal function is required.

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PSD95-SMASh mice have the SMASh cassette replacing the endogenous STOP codon of the Dlg4 gene. The SMASh (Small Molecule-Assisted Shutoff) cassette contains a cis-cleaving hepatitis C virus (HCV) NS3 protease. After administration of the NS3 inhibitor drug asunaprevir (ASV), subsequently synthesized copies of the SMASh-tagged endogenous protein retain the SMASh tag and thus the entire fusion protein will undergo degradation. This strain is useful for reversible posttranslational temporally restricted shut off new PSD95 expression within a drug-specified window and to study the contribution of newly synthesized synaptic proteins to plasticity and memory.

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