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Han, V. Z.

Publications and source records attributed to Han, V. Z..

2 recordsLinked to original sources

Ontogeny of Projections from the Motor Cortex Governing Whisker and Neck Movements to the Striatum in the Rat

Corticostrial or cortico-basal ganglia circuitry plays an important role in integrating sensory and motor information, developing appropriate goal-directed behavior, promoting the maturation of GABAergic interneurons in the striatum, and regulating the nigrostriatal pathways. Dysfunction of this circuitry has been seen in some movement disorders. However, the dynamic changes of this circuitry in early life are not fully elucidated. Previous studies demonstrated that projections from motor cortices of caudal forelimb and jaw-lip-tongue areas to the striatum developed postnatally with terminal-like fibers evident at postnatal day 7. Here we report the development of the projections from the motor cortex governing whisker and neck movements to the striatum. Corticostriatal projections from this area were mainly ipsilateral and also underwent a progressive, postnatal development. The pyramidal tract and its collaterals to the dorsal striatum appeared on the day of birth (postanatal day 0 (P0)), peaked on P6 in density, and continued to be tuned until P36. The intertelencephalic projections in the dorsolateral striatum were established between P6 and P12 and continued to be refined between P20 and P36. Neurons in this motor cortex sent their axons to the contralateral motor cortex via the corpus callosum at the age between P6 and P12. Our results suggest that the time window between P6 and P12 is critical for the development of the projections from the motor cortex governing whisker and neck movement to the striatum in the rat. The overall process of the development of this circuitry appears to correspond to the functional development of whisker movement and locomotor activities.

neuroscience↗

Suppression of PIK3CA-driven epileptiform activity by acute pathway control

Patients harboring mutations in the PI3K-AKT-MTOR signaling pathway often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion of them remain unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing patient-related activating mutation in PIK3CA are epileptic and acutely treatable with PI3K inhibition, irrespective of dysmorphology (Roy et al. 2015). Using the same mutant model, we have now identified physiological mechanisms underlying the dysregulated neuronal excitability and its acute attenuation. We show that Pik3ca-driven hyperexcitability in hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. These are distinct from mechanisms driving epilepsy in TSC/RHEB models. Further, we report that acute inhibition of PI3K or AKT, but not MTOR, suppresses the intrinsic epileptiform nature of the mutant neurons. These data represent an important step towards precision therapeutics against intractable epilepsy, using pathway drugs originally developed as anti-cancer agents.

neuroscience↗