Interneurons from embryonic development to cell-based therapy

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.

Fig. 1. Interneuron transplantation augments interneuron population size and increases inhibition in the host nervous system

(A) Section from the mouse cerebral cortex depicting transplanted interneurons, labeled by a red fluorescent protein. Transplanted immature interneurons disperse, survive, and develop extensive arborizations throughout the parenchyma of the host neocortex. Image width, ~400 μm. (B) Section from the mouse cerebral cortex depicting host interneurons (labeled by green fluorescent protein) and interneurons transplanted from the embryonic ventral telencephalon (red). Image width, ~800 μm. (C) Immature interneurons (red) disperse, survive, and integrate into the postnatal nervous system, where they increase the host cortical interneuron population (green) by up to 35% (40). (D) Transplanted interneurons receive excitatory synapses from host pyramidal neurons and make inhibitory synapses onto host pyramidal neurons. Simultaneous electrode recordings from a transplanted inhibitory neuron (red) and host pyramidal neurons (white). Stimulation of a host pyramidal neuron elicits excitatory postsynaptic potentials in the transplanted interneuron (red). Depolarization of the transplanted interneuron evokes inhibitory postsynaptic potentials in a postsynaptic host pyramidal neuron. Scale bars, 25 ms and 90 mV (presynaptic), 25 ms and 0.125 mV (postsynaptic). (E) Interneuron transplantation increases the frequency of inhibitory signaling events in host pyramidal neurons. Representative traces of inhibitory postsynaptic currents were recorded from host pyramidal neurons in vitro (left, control; right, transplant recipient). [(B) and (C) from (40), (D) from (43), (E) from (33)]

Fig. 2. Transplanted embryonic interneurons retain and execute intrinsic developmental programs when grafted into the postnatal brain

During mouse cortical development, inhibitory neurons undergo a pattern of cell death that peaks around postnatal days 7 to 11, when they reach an intrinsic cellular age of approximately 11 to 18 days (black curve). Later, around postnatal day 28, when surviving inhibitory neurons are approximately 33 to 35 days of age, a critical period for ocular dominance plasticity occurs in the visual cortex (black circles). When newborn inhibitory neurons are transplanted from the embryo into the postnatal brain (red), they undergo a similar pattern of cell death, which reaches a maximum when the transplanted cells are likewise approximately 15 days old (40). Moreover, when transplanted interneurons reach a cellular age of approximately 33 to 35 days, they induce ocular dominance plasticity in the host visual cortex (43). These findings suggest that interneuron development is governed by developmental programs that are established in the embryo, and that when transplanted, embryonic interneurons retain and carry out these developmental programs in the postnatal host nervous system.

Fig. 3. Sources of immature interneurons for transplantation and therapeutic targets

(A and B) Immature interneurons can be transplanted (A) directly from the medial ganglionic eminence (MGE) of the embryonic ventral forebrain, or (B) from in vitro systems in which immature interneurons are generated from embryonic stem (ES) or induced pluripotent stem (IPS) cells. (C) Interneuron transplantation has been studied in diverse regions of the central nervous system, including the striatum, neocortex, hippocampus, and spinal cord. Depending on the site of transplantation, interneurons have been shown to modify disease phenotypes in animal models of Parkinson’s disease, epilepsy, schizophrenia, anxiety disorder, and chronic pain. Interneuron transplantation may also be a method for therapeutically modifying neural circuits in conditions such as Huntington’s disease, amblyopia, stroke, Alzheimer’s disease, and spasticity.