Epidemiologically, adverse early-life experiences, especially chronic early-life stress (CES), may have a lifelong impact on cognitive and emotional functions (Molet et al., 2014, Lor, 2023). Non-human and human studies have demonstrated the adverse effects of early-life stress (ELS) on emotional regulation and related neuronal circuits (Kiser, 2019, Mayer, 2019, Hoover and Kaufman, 2018, Puetz, 2014, Sacu, 2024). Currently, with the diagnostic improvements and increased awareness and monitoring of the condition, ELS has been found to influence the development of cognitive disorder (Lee and Han, 2019, Peralta, 2024)and environmental factors may impact the autism spectrum disorder prevalence in terms of genetic composition (Levy et al., 2009, Agrawal et al., 2018). In humans, the development of the brain network is sensitive to early-life adversities, in which early-life stresses, such as poverty, parental bereavement, maternal substance abuse, and maternal depression, are highly associated with susceptibility to mental illnesses in a later life (Molet et al., 2014, Hoeijmakers et al., 2014, Halligan et al., 2007, Kaplan, 2001). In rodents, a disruption of mother–child interactions during the first 1–2 weeks of life can lead to permanent alterations in many neurobehavioral systems (Molet et al., 2014, Lee and Han, 2019, Sarkar et al., 2019). However, findings regarding the specific mechanism remain inconsistent and how these ELS experiences impact the neural circuits awaits further exploration.

To date, the dysfunction of the GABAergic neural circuit has been implicated in various neurodevelopmental and mental diseases, such as autism, schizophrenia and epilepsy (Di, 2020, Brondino, 2016, de Jonge et al., 2017, Gao and Penzes, 2015). Moreover, animal models of autism spectrum disorders indicate that the dysfunction of the GABAergic signaling pathway in specific neural circuits may account for most of the clinical symptoms in autistic patients (Sgadò, 2013, Cellot and Cherubini, 2014).The balance of excitation-inhibition neural circuits is particularly important for proper social and emotional behaviors, language processing, and advanced cognition (Di, 2020, Reilly et al., 2017). In rodents, during the early-life stage, there is a functional disruption of the GABAergic system, which manifests as a decrease in the number of GABAergic neurons and impaired GABAergic transmission within the hippocampus (Kim, 2024, Gil, 2024), can significantly affect the development, maturation, migration of progenitors' neurons, and break the balance of neural circuits (Chao, 2010, Gustorff et al., 2021, Schuster, 2019).Taken together, these findings evidence that a disruption in the GABAergic signaling pathway can be a potential underlying mechanism that leads to social and cognitive disorder.

Although the etiology of social and cognitive impairment caused by early stress is complex, comprehensive evidence from genetics, autopsy, imaging, and preclinical studies suggests that dysfunction of GABAergic system may be implicated in the social and cognitive disorder pathogenesis (Menezes, 2024, Topchiy, 2024),which highlights that targeting the GABAergic system may serve as a new alternative for the treatment. Interneuron precursors can survive in, migrate, and integrate into the cortical circuitry, featuring a GABAergic phenotype after being transplanted into the brain (Kepecs and Fishell, 2014, Gonzalez-Ramos, 2022). In rodents, originating from the medial ganglia eminence (MGE) and caudal ganglia eminence (CGE), most GABAergic interneurons originate from a single posterior structure, which is formed by the fusion of the MGE during embryonic development (Zhu, et al., 1991). The premise of using embryonic medial ganglionic eminence (MGE) progen foritors cell transplantation was first confirmed by Wichterle and colleagues. They used mouse embryo MGE progenitors and found they could generate GABAergic interneurons when transplanted into the cortex of host pups on postnatal day 2 (P2). The MGE, a temporary embryonic structure located in the sub-pallial proliferative zone, gives rise to progenitor cells that migrate tangentially in streams to colonize the neocortex, hippocampus, and striatum. Once in these regions, MGE progenitors differentiate into two main types of GABAergic interneurons: (1) parvalbumin (PV)-expressing fast-spiking interneurons like basket and chandelier cells, and (2) somatostatin (SST)-expressing interneurons represented mainly by Martinotti cells. Like in normal development, transplanted MGE progenitors show strong migration and differentiation abilities. MGE-derived interneurons can functionally integrate into the host brain. They receive synaptic input from endogenous neurons, form proper layer-specific connections with endogenous excitatory neurons, and enhance GABA-mediated inhibition in a subtype-specific manner. Consequently, we propose the hypothesis that enhancing the neurogenesis of GABAergic neurons in the hippocampus could represent a promising therapeutic approach for the treatment of social and cognitive disorders.

As cell-based therapies have received much attention for their potential to treat a variety of complex neurological disorders (Zhu, et al., 1991, Tong, 2014, Donegan et al., 2018). In current research, we have established a reliable mouse early stress model that simulates common early stress events in the population through early maternal infant separation and a four week chronic unpredictable mild stress (CUMS) program, and evaluated core symptoms of social and cognitive impairment through a series of behavioral experiments, including communication disorders, mental retardation repetitive stereotyped movements and mood disorder like anxiety. We found that MGE cell therapy successfully ameliorated the social and cognitive behavior of stressed mice, increased the amount of GABAergic neurons in the hippocampus, and upregulated the levels of synaptic related proteins such as Reelin, Fyn, PSD95, and SYN. These findings indicate that the transplantation of medial ganglionic eminence (MGE) cells into the hippocampus represents a promising therapeutic strategy for addressing social and cognitive deficits.