Interneuron Transplantation Creates New Network States and Rescues Social Behavior Deficits in a Mouse Model of Autism

Abstract

Objectives: The dysfunction of GABAergic interneurons, or "interneuronopathy," has been implicated in autism pathophysiology. Treatments that ameliorate or compensate for interneuron dysfunction may thus constitute a novel approach to autism therapy. When transplanted from the embryonic ventral forebrain, interneuron precursors migrate and survive in the postnatal cerebral cortex, where they differentiate into mature GABAergic interneurons, form functional synapses, increase inhibitory signaling onto recipient neurons, and modify experience-dependent plasticity. Interneuron transplantation has been shown to modify disease phenotypes in animal models, but it remains unclear whether it elicits therapeutic effects by reversing pre-existing circuit abnormalities, nonspecifically increasing synaptic inhibition, or engaging mechanisms that vary depending on recipient background and behavioral state. Furthermore, the impact of interneuron transplantation on autism-like phenotypes has not been assessed. The objective of this study was to characterize the behavioral and physiologic impacts of interneuron transplantation in a mouse genetic model of autism. Method(s): We transplanted embryonic interneuron precursors from the medial ganglionic eminence into the prefrontal cortex of neonatal mice. Transplantation was performed into wild type mice and mice that lacked Pten, a high confidence autism gene, in interneurons derived from the medial ganglionic eminence. We assessed the effects of transplantation on recipient behavioral phenotypes, cellular electrophysiology in vitro, and network oscillations in vivo; and we characterized the histochemical identities of the surviving transplant population. Result(s): Transplantation rescued Pten mutant social behavior deficits without normalizing excessive synaptic inhibition or reduced baseline state gamma oscillatory power. However, transplantation increased social interaction-evoked EEG activity to levels exceeding those observed in sham-treated wild type and mutant mice. When interneurons were transplanted into wild type recipients, it did not modify social behavior, baseline state EEG signals, or social interaction-evoked EEG signals. The subtype composition of the surviving transplanted population also varied between Pten mutant recipients and wild type recipients. Conclusion(s): Interneuron transplantation elicits recipient-and behavioral state-dependent effects, and it may normalize behavior by creating new patterns of network activity rather than restoring wild-type states. Our findings suggest that interneuron transplantation may represent a novel cell-based therapy for autism, and they define mechanistic considerations relevant to the design of interneuron transplantation studies.