Choroid-Plexus-Derived Otx2 Homeoprotein Constrains Adult Cortical Plasticity

Abstract

Summary Brain plasticity is often restricted to critical periods in early life. Here, we show that a key regulator of this process in visual cortex, Otx2 homeoprotein, is synthesized and secreted globally from the choroid plexus. Consequently, Otx2 is maintained in selected GABA cells unexpectedly throughout the mature forebrain. Genetic disruption of choroid-expressedOtx2 impacts these distant circuits and in primary visual cortex reopens binocular plasticity to restore vision in amblyopic mice. The potential to regulate adult cortical plasticity through the choroid plexus underscores the importance of this structure in brain physiology and offers novel therapeutic approaches to recovery from neurodevelopmental disorders more broadly.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Choroid plexus-derived Otx2 is widely distributed throughout the brain and is taken up by parvalbumin + neurons, where it regulates the maturation of neural circuitry and critical periods of plasticity in the visual cortex. Blocking release of Otx2 from the choroid plexus in the adult reopens binocular plasticity in the visual cortex [140]. Thus, choroid plexus-derived factors may globally affect neural circuit formation, activity and plasticity during critical periods, as well as in the adult brain.…”

Postnatal signalling with homeoprotein transcription factors

“…Indeed, closing an eye following either protocol can install amblyopia in the adult mouse and, more interestingly, the same protocols restore visual acuity and binocular vision in amblyopic mice [9,30]. Interestingly, reactivation of plasticity was also obtained by hydrolysing the complex sugars present in PNNs [33].…”

“…In a collaborative study with the group of Takao Hensch, it was observed that Otx2 content increases in PV cells in parallel with their maturation [29]. Interestingly, this content does not result from local Otx2 expression but from its import from external sources, such as the choroid plexus or, possibly, the retina [29,30].…”

“…This scheme (a temporal version of the French Flag Problem [32]) has the consequence that Otx2 import is necessary throughout adulthood to maintain the CP for binocular vision in a closed state (figure 2a). In a search for sources of adult Otx2, the choroid plexus, a site of high Otx2 expression at all developmental stages and throughout adulthood, was identified and found to release Otx2 into the ventricles of the adult brain [30]. Indeed, recombining Otx2 in the adult choroid plexus reduces Otx2 content in PV cells [30].…”

“…In a search for sources of adult Otx2, the choroid plexus, a site of high Otx2 expression at all developmental stages and throughout adulthood, was identified and found to release Otx2 into the ventricles of the adult brain [30]. Indeed, recombining Otx2 in the adult choroid plexus reduces Otx2 content in PV cells [30].…”