In rodent brain slices, activity-dependent exocytosis of NT from presynaptic terminals-followed by agrin cleavage-induces the formation of dendritic filopodia. Synaptic agrin is cleaved by NT at two sites, yielding a 110 kDa N-terminal fragment, a 90 kDa internal fragment, and a 22 kDa C-terminal fragment. At present, the only known proteolytic substrate of NT is the proteoglycan agrin. Interestingly, the proteolytic activity of NT requires coincident activation of postsynaptic NMDA receptors, i.e., its activation presumably occurs in a Hebbian manner. Live imaging studies in cultured hippocampal neurons revealed that NT is recruited and released presynaptically in an activity-dependent manner. By electron microscopy, NT was localized at the presynaptic terminals of human cortical synapses. In the developing mouse brain, postnatal NT mRNA is strongly expressed in the cortex and hippocampus, reaching its peak expression during neural development and correlating with periods of synaptogenesis. In the adult central nervous system (CNS) of humans, NT mRNA is highly expressed in the hippocampus (particularly in the subiculum and pyramidal cells of the CA1 region), cerebral cortex, and amygdala. Neurotrypsin (NT), a neuronal trypsin-like serine protease, has been recognized to play an essential role in cognitive brain function due to a 4-nucleotide deletion in the PRSS12 gene of the human chromosome 4q, which results in an earlier stop codon and the production of a truncated protein leading to severe mental retardation in humans. Multiple studies have implicated the role of extracellular proteases in synaptic plasticity, learning, and memory. Moreover, agrin-22 co-aggregates with pre- and postsynaptic markers and increases the density and size of presynaptic boutons and presynaptic puncta, corroborating the view that agrin-22 supports the synaptic growth. In vivo delivery of adeno-associated virus expressing an NT-generated fragment of agrin, agrin-22, but not a shorter agrin-15, elevates the spine density in NT −/− mice. The head width of thin spines is reduced in both juvenile and aged NT −/− mice. Structurally, juvenile mutants exhibit reduced spine density in the CA1 region, fewer thin spines, and no modulation in the density of dendritic spines following fear conditioning and extinction in contrast to wild-type littermates. The latter persists in aged NT −/− mice, which, unlike juvenile mice, show normal recall but impaired extinction of contextual fear memories. ![]() Behaviorally, juvenile NT −/− mice show impaired contextual fear memory and have a sociability deficit. We report that juvenile neurotrypsin-deficient (NT −/−) mice exhibit impaired long-term potentiation induced by a spaced stimulation protocol designed to probe the generation of new filopodia and their conversion into functional synapses. Here, we investigated the functional importance of this mechanism for synaptic plasticity, learning, and extinction of memory. NT is activated in vitro by Hebbian-like conjunction of pre- and postsynaptic activities, which promotes the formation of dendritic filopodia via proteolytic cleavage of the proteoglycan agrin. Neurotrypsin (NT) is a neuronal trypsin-like serine protease whose mutations cause severe mental retardation in humans.
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