The receptor tyrosine kinases represent an important class of signal transduction molecules that have been shown to play critical roles in neural development. We report in the present study that the neuregulin receptor ErbB4 is preferentially expressed by interneurons that are migrating tangentially from the ventral to the dorsal rat telencephalon. ErbB4 immunoreactivity was detected in the medial ganglionic eminence as early as embryonic day (E) 13 at the inception of tangential migration. Prominent ErbB4-positive migratory streams consisting of cells double-labeled with ErbB4 and Dlx, a marker of tangentially migrating cells, were found to advance along the lower intermediate zone and the marginal zone from the ventrolateral to the dorsomedial cortex at E16–E18. After E20, the ErbB4-positive stream in the lower intermediate zone shifted towards the germinal zone and further extended via the cortex into the hippocampal primordium. ErbB4 was not expressed by Tbr1-positive glutamatergic projection neurons during development. ErbB4 was preferentially expressed by the majority of parvalbumin-positive interneurons and subsets of other GABAergic interneurons in the cerebral cortex and the hippocampus in adulthood. The early onset and preferential expression of ErbB4 in tangentially migrating interneurons suggests that neuregulin/ErbB4 signaling may regulate the development and function of telencephalic interneurons.

Chen et al. found that Foxp2 interacts with Mef2c to wire synaptic circuits linking neocortex to basal ganglia. The study analyzes the basics of circuit wiring underlying vocal communication. Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder, in which language function can be severely affected. We demonstrate that in the mouse striatum, the gene Foxp2 negatively interacts with the synapse suppressor gene 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.

Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or “patch”) and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which retinoid receptor signaling controls compartmental formation in the striatum. We analyzed RARβ ^−/− mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARβ signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G ₁ to S phase, and also reduction of the proneural gene Mash1 , which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARβ selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARβ ^−/− mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARβ signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control.

Significance: Basal ganglia circuits are engaged in controlling psychomotor function. The circuits consist of striatonigral and striatopallidal pathways. The opposing but balanced activity of these two neural pathways is important for regulating movement-related functions. How the cell types of striatonigral and striatopallidal neurons are specified to construct these two pathways during development remains elusive. We found that the LIM homeodomain transcription factor Islet-1 (Isl1) was specifically expressed in striatonigral neurons during development. Genetic inactivation of Isl1 resulted in increased apoptosis, abnormal differentiation, and aberrant axonal projections of striatonigral neurons. These findings suggest that Isl1 plays a key role in specification of striatonigral neurons. Our study provides insights into genetic mechanisms by which basal ganglia circuits are built to function.

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 [ i.e. , 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 ^E12.75 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 ^E12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA ^E12.75 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 ^E12.75 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 ^E12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via 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. FASEB J. 31, 4458–4471 (2017). www.fasebj.org