Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior.

Tuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. In contrast, only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism.