Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder (ASD), in which language function can be severely affected. We demonstrate that in the striatum, the gene, Foxp2, negatively interacts with the synapse suppressor, Mef2C. We present causal evidence that Mef2C inhibition by Foxp2 in neonatal mouse striatum controls synaptogenesis of corticostriatal inputs and vocalization in neonates. Mef2C suppresses corticostriatal synapse formation and striatal spinogenesis, but can, itself, be repressed by Foxp2 through direct DNA binding. Foxp2 deletion de-represses Mef2C, and both intrastriatal and global decrease of Mef2C rescue vocalization and striatal spinogenesis defects of Foxp2-deletion mutants. These findings suggest that Foxp2-Mef2C signaling is critical to corticostriatal circuit formation. If found in humans, such signaling defects could contribute to a range of neurologic and neuropsychiatric disorders.

The striatum is a key hub in the basal ganglia for processing neural information from the sensory, motor, and limbic cortices. The massive and diverse cortical inputs entering the striatum allow the basal ganglia to perform a repertoire of neurological functions ranging from basic level of motor control to high level of cognition. The heterogeneity of the corticostriatal circuits, however, also renders the system susceptible to a repertoire of neurological diseases. Clinical and animal model studies have indicated that defective development of the corticostriatal circuits is linked to various neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and schizophrenia. Importantly, many neuropsychiatric disease-risk genes have been found to form the molecular building blocks of the circuit wiring at the synaptic level. It is therefore imperative to understand how corticostriatal connectivity is established during development. Here, we review the construction during development of these corticostriatal circuits at the synaptic level, which should provide important insights into the pathogenesis of neuropsychiatric disorders related to the basal ganglia and help the development of appropriate therapies for these diseases.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with a high prevalence rate. The core symptoms of ASD patients are impaired social communication and repetitive behavior. Genetic and environmental factors contribute to pathophysiology of ASD. Regarding environmental risk factors, it is known that valproic acid (VPA) exposure during pregnancy increases the chance of ASD among offspring. Over a decade of animal model studies have shown that maternal treatment with VPA in rodents recapitulates ASD-like pathophysiology at a molecular, cellular and behavioral level. Here, we review the prevailing theories of ASD pathogenesis, including excitatory/inhibitory imbalance, neurotransmitter dysfunction, dysfunction of mTOR and endocannabinoid signaling pathways, neuroinflammation and epigenetic alterations that have been associated with ASD. We also describe the evidence linking neuropathological changes to ASD-like behavioral abnormalities in maternal VPA-treated rodents. In addition to obtaining an understanding of the neuropathological mechanisms, the VPA-induced ASD-like animal models also serve as a good platform for testing pharmacological reagents that might be use treating ASD. We therefore have summarized the various pharmacological studies that have targeted the classical neurotransmitter systems, the endocannabinoids, the Wnt signal pathway and neuroinflammation. These approaches have been shown to often be able to ameliorate the ASD-like phenotypes induced by maternal VPA treatments.

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic system-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [, maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor-positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPA treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPA treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPA treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress-induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPA pups. Collectively, dysfunctional corticostriatal pathways, particularly the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.-Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

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The striatum comprises a mosaic structure of striosomal and matrix compartments. Imbalanced neuronal activity between striosomes and matrix is implicated in neurological deficits in psychomotor and limbic functions. Because patients with autism spectrum disorder (ASD) are impaired in social communication and psychomotor function, it raises the possibility that abnormal striatal compartments may contribute to ASD pathogenesis. Here, we provide pathological evidence from human postmortem brains to support this hypothesis. Because ASD is a neurodevelopmental disease that emerges early in childhood, we analyzed juvenile and adolescent brains. Distinct patterns of PRODYNORPHIN-positive and calbindin-poor striosomes were detected in the caudate nucleus of control brains by in situ hybridization and immunohistochemistry. By contrast, PRODYNORPHIN-positive and calbindin-poor striosomes were decreased in the caudate nucleus of young ASD brains. Moreover, calbindin, a matrix marker, was aberrantly increased in the striosomal compartment, obscuring the boundaries between calbindin-poor striosomes and calbindin-rich matrix in ASD caudate nucleus. Calbindin-positive cells were decreased in the ASD matrix compartment. Collectively, our study has uncovered for the first time that aberrant striatal compartments occur in the caudate nucleus of human ASD brains, which suggests abnormal striatal compartmentation as a pathological signature that has previously been underestimated in ASD pathogenesis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD.

Many genes are expressed in embryonic brains, and some of them are continuously expressed in the brain after birth. For such persistently expressed genes, they may function to regulate the developmental process and/or physiological function in neonatal brains. To investigate neurobiological functions of specific genes in the brain, it is essential to inactivate genes in the brain. Here, we describe a simple stereotaxic method to inactivate gene expression in the striatum of transgenic mice at neonatal time windows. AAV-eGFP-Cre viruses were microinjected into the striatum of Ai14 reporter gene mice at postnatal day (P) 2 by stereotaxic brain surgery. The tdTomato reporter gene expression was detected in P14 striatum, suggesting a successful Cre-loxP mediated DNA recombination in AAV-transduced striatal cells. We further validated this technique by microinjecting AAV-eGFP-Cre viruses into P2Foxp2 mice. Double labeling of GFP and Foxp2 showed that GFP-positive cells lacked Foxp2 immunoreactivity in P9 striatum, suggesting the loss of Foxp2 protein in AAV-eGFP-Cre transduced striatal cells. Taken together, these results demonstrate an effective genetic deletion by stereotaxically microinjected AAV-eGFP-Cre viruses in specific neuronal populations in the neonatal brains of floxed transgenic mice. In conclusion, our stereotaxic technique provides an easy and simple platform for genetic manipulation in neonatal mouse brains. The technique can not only be used to delete genes in specific regions of neonatal brains, but it also can be used to inject pharmacological drugs, neuronal tracers, genetically modified optogenetics and chemogenetics proteins, neuronal activity indicators and other reagents into the striatum of neonatal mouse brains.