Abstract
During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these “transfer” sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.
Highlights
During postnatal life, the cerebral cortex passes through critical periods (CPs) of plasticity allowing the neuronal circuitry to shape in response to environmental stimuli
Lipophilic agents can do without cell-surface receptors due to their ability to diffuse through the plasma membrane, but this is normally not the case for proteins, which cannot pass the membrane barrier
Homeoprotein transcription factors represent an exception as they are secreted and internalized by live cells owing to two peptidic domains
Summary
The cerebral cortex passes through critical periods (CPs) of plasticity allowing the neuronal circuitry to shape in response to environmental stimuli. CPs are driven by the maturation of a subset of inhibitory interneurons, the fast-spiking parvalbumin-expressing GABAergic neurons (PV cells), present in layers III and IV of the cerebral cortex [1]. Plasticity terminates with the full maturation of PV cells and the consolidation of the Excitation/ Inhibition (E/I) cortical balance [2]. CPs for different sensory, motor or cognitive behaviors are spread out during postnatal development and open and close at different times [3]. Plasticity for the establishment of binocular vision opens at post-natal day 20 (P20) and closes at P40 [4]. Closing one eye during this period (but not before P20 or after P40) leads to an irreversible loss of visual acuity for the temporarily closed eye, a state known as amblyopia, which affects 3% of the human population
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