SUMMARY Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. Most differentiated populations, however, exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and post-transplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to seven months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease.

Cortical inhibitory circuits are formed by GABAergic interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis1-5, is that cortical interneurons are overproduced, and then following their migration into cortex, excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we have characterized the developmental cell death of mouse cortical interneurons in vivo, in vitro, and following transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax- (Bcl-2 associated X-) dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Remarkably, over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by central nervous system (CNS) neurons6-8. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Together, our findings indicate that interneuron cell death is intrinsically determined, either cell-autonomously, or through a population-autonomous competition for survival signals derived from other interneurons.

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Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.epilepsy ͉ inhibition ͉ neocortex ͉ therapy ͉ graft

Critical periods are times of pronounced brain plasticity. During a critical period in the postnatal development of the visual cortex, the occlusion of one eye triggers a rapid reorganization of neuronal responses, a process known as ocular dominance plasticity. We have shown that the transplantation of inhibitory neurons induces ocular dominance plasticity after the critical period. Transplanted inhibitory neurons receive excitatory synapses, make inhibitory synapses onto host cortical neurons, and promote plasticity when they reach a cellular age equivalent to that of endogenous inhibitory neurons during the normal critical period. These findings suggest that ocular dominance plasticity is regulated by the execution of a maturational program intrinsic to inhibitory neurons. By inducing plasticity, inhibitory neuron transplantation may facilitate brain repair.Once in life, a critical period for ocular dominance plasticity is initiated by the development of intracortical inhibitory synaptic transmission (1). Reduction of inhibitory transmission disrupts ocular dominance plasticity (2), whereas the early enhancement of inhibitory transmission promotes a precocious period of ocular dominance plasticity (3-6). After the critical period has passed, however, direct pharmacological augmentation of inhibitory transmission does not induce plasticity (7).Cortical inhibitory neurons are produced in the medial and caudal ganglionic eminences of the embryonic ventral forebrain (8-10). When transplanted into the brains of older animals, embryonic inhibitory neuron precursors disperse widely (11) and develop the characteristics of mature cortical inhibitory neurons (12). We have used repeated optical imaging of intrinsic signals (13,14) to examine whether inhibitory neuron transplantation produces ocular dominance plasticity after the critical period ( fig. S1).In mice, ocular dominance plasticity reaches a peak in the fourth postnatal week, when cortical inhibitory neurons are ~33 to 35 days old (3, 10) (Fig. 1A) (Fig. 1B, open black circles). After four days of visual deprivation of the contralateral eye, cortical responses were shifted toward the ipsilateral eye, with a mean ODI value of 0.00 (Fig. 1B, filled black circles).We first examined whether inhibitory neuron transplantation induced ocular dominance plasticity 14 to 18 days after the critical period, at P42 to 46. We transplanted cells from the embryonic day 13.5 to 14.5 (E13.5 to 14.5) medial ganglionic eminence (MGE) into sites flanking the host primary visual cortex at two ages, P0 to 2 and P9 to 11, respectively (Fig. 1A). Host mice that received transplants at P9 to 11 were thus studied 33 to 35 days after transplantation (DAT), whereas hosts that received transplants at P0 to 2 were studied 43 to 46 DAT. Transplantation did not alter the absolute magnitudes of visual responses in the host binocular visual cortex ( fig. S2). Before monocular deprivation, host cortex responded more to the contralateral eye ( (15, 16). These findings demonstrate that t...

Many neurologic and psychiatric disorders are marked by imbalances between neural excitation and inhibition. In the cerebral cortex, inhibition is mediated largely by GABAergic (γ-aminobutyric acid–secreting) interneurons, a cell type that originates in the embryonic ventral telencephalon and populates the cortex through long-distance tangential migration. Remarkably, when transplanted from embryos or in vitro culture preparations, immature interneurons disperse and integrate into host brain circuits, both in the cerebral cortex and in other regions of the central nervous system. These features make interneuron transplantation a powerful tool for the study of neurodevelopmental processes such as cell specification, cell death, and cortical plasticity. Moreover, interneuron transplantation provides a novel strategy for modifying neural circuits in rodent models of epilepsy, Parkinson’s disease, mood disorders, and chronic pain.

P lasticity, or the ability to change in response to experience, is an inherent feature of the brain that allows for the development and maintenance of nervous system function. 27 Brain plasticity manifests itself through various mechanisms at different levels; representative examples for such mechanisms at the molecular, cellular, and tissue levels, respectively, include trafficking of neurotransmitter receptors, the rearrangement of neuronal axons and dendrites, and the generation of new neurons and glia.5 Animal experiments have characterized brain plasticity and described its mechanistic basis in nonhuman subjects, but few detailed and direct investigations of plasticity have been made in humans. 12,14,18,27 A greater knowledge of human brain plasticity, particularly in the setting of disease, is fundamental to understanding the clinical course of neurological conditions, to applying abbreviatioNs ADP = after-discharge potential; DES = direct electrical stimulation; FLAIR = fluid-attenuated inversion-recovery; fMRI = functional MRI; GTR = grosstotal resection; PET = positron emission tomography; STR = subtotal resection; TMS = transcranial magnetic stimulation; WHO = World Health Organization. Intraoperative mapping during repeat awake craniotomy reveals the functional plasticity of adult cortex *derek g. southwell, md, phd, shawn l. hervey-Jumper, md, david w. perry, phd, and mitchel s. berger, md Department of Neurological Surgery, University of California, San Francisco, California obJective To avoid iatrogenic injury during the removal of intrinsic cerebral neoplasms such as gliomas, direct electrical stimulation (DES) is used to identify cortical and subcortical white matter pathways critical for language, motor, and sensory function. When a patient undergoes more than 1 brain tumor resection as in the case of tumor recurrence, the use of DES provides an unusual opportunity to examine brain plasticity in the setting of neurological disease. methods The authors examined 561 consecutive cases in which patients underwent DES mapping during surgery for glioma resection. "Positive" and "negative" sites-discrete cortical regions where electrical stimulation did (positive) or did not (negative) produce transient sensory, motor, or language disturbance-were identified prior to tumor resection and documented by intraoperative photography for categorization into functional maps. In this group of 561 patients, 18 were identified who underwent repeat surgery in which 1 or more stimulation sites overlapped with those tested during the initial surgery. The authors compared intraoperative sensory, motor, or language mapping results between initial and repeat surgeries, and evaluated the clinical outcomes for these patients. results A total of 117 sites were tested for sensory (7 sites, 6.0%), motor (9 sites, 7.7%), or language (101 sites, 86.3%) function during both initial and repeat surgeries. The mean interval between surgical procedures was 4.1 years. During initial surgeries, 95 (81.2%) of 117 sites were found to...

We report excellent long-term seizure control outcomes after surgery for gangliogliomas. Intraoperative electrocorticography may be a useful adjunct for guiding extended resection in certain pharmacoresistant epilepsy patients with gangliogliomas. Subtotal resection is associated with higher rates of tumor progression and nonoptimal seizure outcomes.