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.

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.

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.

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