Review

Interneurons from Embryonic Development to Cell-Based Therapy

Science  11 Apr 2014:
Vol. 344, Issue 6180, pp.
DOI: 10.1126/science.1240622

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Structured Abstract

Background

Alterations in neural excitation and inhibition cause a number of neurologic and psychiatric disorders. In the cerebral cortex, excitation and inhibition are mediated by two cell types born in distinct areas of the embryo: excitatory projection neurons, which are generated in the developing cortex, and inhibitory interneurons, which are produced outside the cortex in the ventral forebrain. After migrating from their origins across the developing brain, young interneurons reach the cortex and differentiate into various inhibitory neuronal cell types. Roughly two-thirds of these young cells survive in the cortex to form the local inhibitory circuits that shape excitatory neuron activity. The embryologic programs that guide interneuron migration, survival, and circuit integration are also executed by these young neurons after their transplantation into the juvenile and adult nervous systems. These processes, realized in the developmentally and topographically distinct environment of the recipient, offer a unique opportunity for studying neurodevelopment and therapeutically modifying neural circuits.

Embedded Image

Transplanted interneurons for the study of neural development and the treatment of nervous system disorders. Precursors of inhibitory interneurons transplanted from the medial ganglionic eminence of the ventral embryonic forebrain into the juvenile or adult rodent cortex migrate from the graft site and become dispersed throughout the recipient tissue (shown as small red dots in the transplanted hemisphere in a cross section of the rodent brain, upper left). In the recipient, transplanted interneurons follow cell-intrinsic programs that normally regulate their survival and differentiation in the embryo. Interneurons in the host brain (small green dots) do not die as a result of the additional neurons; rather, transplantation increases the total interneuron population. Transplanted interneurons develop axonal and dendritic arbors (red cell magnified in foreground), synaptically integrate into neural circuits, and modify inhibitory signaling. Interneuron transplantation provides a method for studying neural circuit assembly and function and is a potential cell-based therapy for conditions such as epilepsy, Parkinson’s disease, schizophrenia, anxiety, and chronic pain.

Advances

In both neonatal and adult rodents, transplanted embryonic interneurons have been shown to migrate and survive in diverse neural structures, including the cerebral cortex and the spinal cord. Transplanted interneurons form elaborate processes in host tissues, receive synaptic inputs, and make inhibitory connections with host neurons, similar to what they do in their normal setting. Functionally, transplantation has been used to modify inhibitory signaling in the host brain and to induce reorganization of the cortex by creating new windows of neural circuit plasticity. Transplanted interneurons have been shown to modify disease phenotypes in several rodent models of neurologic and psychiatric disorders, including epilepsy, chronic pain, Parkinson’s disease, schizophrenia, and anxiety. Interneuron transplantation has also been used to explore how cell-intrinsic and environmental factors interact to govern cellular fate and circuit formation. To generate interneurons for possible clinical applications, researchers are developing in vitro culture systems for the derivation of interneurons from embryonic stem cells and induced pluripotent stem cells. These efforts have produced new interneurons that, like their endogenous counterparts, disperse and integrate in the recipient brain after transplantation.

Outlook

Cortical interneurons are a heterogeneous population, and little is known about how distinct subtypes of interneurons function in neural circuits. Thus far, transplantation studies have used donor pools containing large mixtures of interneurons. As the mechanisms underlying interneuron diversity become better understood, donor populations may be selected or produced to include only specific subtypes of cells. This will allow researchers to study the functional roles of different interneuron types and may permit the use of specific donor populations for different pathologies. It is unknown how transplanted interneurons modify disease phenotypes. While transplanted interneurons likely exert therapeutic effects by increasing neural inhibition, other mechanisms are also possible. By transplanting mutant cells, or cells engineered to respond to optogenetic or chemical stimulation, these mechanisms may be elucidated. Eventual clinical applications will require more subtle and detailed studies of the behavioral effects of interneuron transplantation.

Interneurons Reach Far and Wide

Interneurons in the brain have been garnering increasing attention. Southwell et al. (10.1126/science.1240622) review the development of this unique class of neurons. The cells migrate long distances during brain development. Transplantation of interneurons derived from embryonic stem cells is yielding insight into disease processes and may have therapeutic potential. For example, Parkinson's disease, epilepsy, certain psychiatric disorders, and even some sorts of chronic pain either involve interneurons or may respond to transplanted interneurons.

Abstract

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.

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