Deficiency in neprilysin causes laminar impairments in the visual cortex

Abstract

1AbstractNeprilysin (Nep) is a membrane-bound zinc-dependent endopeptidase that cleaves a wide variety of small peptides in the body. In the brain, it has gained fame as an important endogenous degrader of amyloid beta peptide, responsible for the pathophysiology of Alzheimer’s disease. Nep is expressed specifically by parvalbumin (PV)-expressing inhibitory neurons in the adult cortex, the maturation of which regulates critical period plasticity. Given that PV neuron soma and proximal dendrites are primary sites of perineuronal net (PNN) formation, we investigated the role that Nep plays in PNN and PV neuron maturation and cortical development in the mouse visual cortex, using mice whose Nep expression is constitutively knocked out (Nep KO mice). Nep expression is high in young wildtype mice (P10) and is downregulated rapidly throughout postnatal development. It is especially prominent in layer 5 where it is highly expressed by inhibitory neurons and also expressed at low levels by many excitatory neurons. Contrary to our hypothesis, Nep KO mice did not show an alteration in the relative density or gross morphology of PNNs. Instead, Nep KO mice showed reduced maximal activation of L5 after white matter stimulation and decreased number of inhibitory neurons in L4. These laminar defects may lead to impaired development of optomotor acuity in Nep KO mice.