Prenatal deletion of the RNA-binding protein HuD disrupts postnatal cortical circuit maturation and behavior.

The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.

Fate determination of cerebral cortical GABAergic interneurons and their derivation from stem cells.

Cortical GABAergic interneurons modulate cortical excitation, and their dysfunction is implicated in a multitude of neuropsychiatric disorders including autism, schizophrenia and epilepsy. Consequently, the study of cortical interneuron development, and their derivation from stem cells for transplantation therapy, has garnered intense scientific interest. In this review, we discuss some of the molecular signals involved in cortical interneuron fate determination, and describe how this has informed the use of mouse and human embryonic stem cell biology in generating cortical interneurons in vitro. We highlight the tremendous progress that has been made recently using stem cells to derive cortical interneurons, as well as challenges that have arisen. This article is part of a Special Issue entitled SI:StemsCellsinPsychiatry.