In this STEP KO strain, a neo cassette replaces the catalytic site of the protein tyrosine phosphatase, non-receptor type 5 (Ptpn5) gene, abolishing gene expression. Homozygotes are viable, fertile, and normal in size. Striatal enriched protein phosphatase (STEP) is a neuron-specific tyrosine phosphatase which regulates synaptic plasticity following glutamatergic and dopaminergic input. Expressed mainly in the striatum, hippocampus, amygdala, and cortex of the brain, glutamate-activated STEP controls synaptic plasticity through limiting the duration of ERK 1/2 MAP kinase activity and by endocytosis of glutamate receptors. Activation of ERK1/2 in STEP-expressing regions of the brain is required for memory formation and learning. STEP levels are also shown to be increased in prefrontal cortex of Alzheimer's Disease (AD) models. Homozygous STEP KO mice lack expression of all STEP isoforms, and exhibit enhanced phosphorylation of ERK1/2 in the striatum, hippocampus, and amygdala, with slight elevation in the lateral septum. Heterozygous mice display a 50% reduction in STEP expression when compared to wildtype littermates. This decrease in STEP levels reverses cognitive and cellular deficits observed in AD mice, and blocks internalization of glutamate receptors. These mice may be useful for studying the role of STEP in regulating synaptic plasticity in Alzheimer's Disease.
