Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza, T.; Kiziltug, E.; Allington, G.; Barson, D.; O'Connor, D.; Robert, S. M.; Mekbib, K. Y.; Nanda, P.; Greenberg, A.; Singh, A.; Duy, P. Q.; Mandino, F.; Zhao, S.; Lynn, A.; Reeves, B. C.; Marlier, A.; Getz, S. A.; Nelson-Williams, C.; Shimelis, H.; Zhang, J.; Walsh, L. K.; Wang, W.; Smith, H.; OuYang, A.; Deniz, E.; Lake, E.; Jin, S. C.; Luikart, B. W.; Kahle, K. T.

doi:10.1101/2023.03.18.533275

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bioRxiv · 10.1101/2023.03.18.533275

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

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Abstract

Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders. HIGHLIGHTSO_LIPTEN de novo mutations are associated with cerebral ventriculomegaly in autism spectrum disorder (ASD) and congenital hydrocephalus (CH). C_LIO_LIPten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of medial ganglionic eminence Nkx2.1+ neural precursors and CSF hypersecretion from inflammation-induced choroid plexus hyperplasia. C_LIO_LIThe hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. C_LIO_LImTORC1 inhibition via Raptor deletion or early post-natal treatment with rapamycin or everolimus increases survival and ameliorates Pten-mutant ventriculomegaly and cortical pathology. C_LI

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DeSpenza, T., Kiziltug, E., Allington, G., Barson, D., O'Connor, D., Robert, S. M., Mekbib, K. Y., Nanda, P., Greenberg, A., Singh, A., Duy, P. Q., Mandino, F., Zhao, S., Lynn, A., Reeves, B. C., Marlier, A., Getz, S. A., Nelson-Williams, C., Shimelis, H., Zhang, J., Walsh, L. K., Wang, W., Smith, H., OuYang, A., Deniz, E., Lake, E., Jin, S. C., Luikart, B. W., Kahle, K. T.. 2023-03-19. Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants. https://doi.org/10.1101/2023.03.18.533275

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