FOXG1 sequentially orchestrates subtype specification of postmitotic cortical projection neurons.

The mammalian neocortex is a highly organized six-layered structure with four major cortical neuron subtypes: corticothalamic projection neurons (CThPNs), subcerebral projection neurons (SCPNs), deep callosal projection neurons (CPNs), and superficial CPNs. Here, careful examination of multiple conditional knockout model mouse lines showed that the transcription factor FOXG1 functions as a master regulator of postmitotic cortical neuron specification and found that mice lacking functional FOXG1 exhibited projection deficits. Before embryonic day 14.5 (E14.5), FOXG1 enforces deep CPN identity in postmitotic neurons by activating Satb2 but repressing Bcl11b and Tbr1. After E14.5, FOXG1 exerts specification functions in distinct layers via differential regulation of Bcl11b and Tbr1, including specification of superficial versus deep CPNs and enforcement of CThPN identity. FOXG1 controls CThPN versus SCPN fate by fine-tuning Fezf2 levels through diverse interactions with multiple SOX family proteins. Thus, our study supports a developmental model to explain the postmitotic specification of four cortical projection neuron subtypes and sheds light on neuropathogenesis.

Loss of Calretinin in L5a impairs the formation of the barrel cortex leading to abnormal whisker-mediated behaviors.

The rodent whisker-barrel cortex system has been established as an ideal model for studying sensory information integration. The barrel cortex consists of barrel and septa columns that receive information input from the lemniscal and paralemniscal pathways, respectively. Layer 5a is involved in both barrel and septa circuits and play a key role in information integration. However, the role of layer 5a in the development of the barrel cortex remains unclear. Previously, we found that calretinin is dynamically expressed in layer 5a. In this study, we analyzed calretinin KO mice and found that the dendritic complexity and length of layer 5a pyramidal neurons were significantly decreased after calretinin ablation. The membrane excitability and excitatory synaptic transmission of layer 5a neurons were increased. Consequently, the organization of the barrels was impaired. Moreover, layer 4 spiny stellate cells were not able to properly gather, leading to abnormal formation of barrel walls as the ratio of barrel/septum size obviously decreased. Calretinin KO mice exhibited deficits in exploratory and whisker-associated tactile behaviors as well as social novelty preference. Our study expands our knowledge of layer 5a pyramidal neurons in the formation of barrel walls and deepens the understanding of the development of the whisker-barrel cortex system.

Histone deacetylase 3 in hippocampus contributes to memory impairment after chronic constriction injury of sciatic nerve in mice.

ABSTRACT: Chronic neuropathic pain is frequently accompanied by memory impairment, yet the underlying mechanisms remain unclear. Here, we showed that mice displayed memory impairment starting at 14 days and lasting for at least 21 days after chronic constriction injury (CCI) of unilateral sciatic nerve in mice. Systemic administration of the pan histone deacetylase (HDAC) inhibitor sodium butyrate attenuated this memory impairment. More specifically, we found that hippocampus HDAC3 was involved in this process because the levels of its mRNA and protein increased significantly in the hippocampus at 14 and 21 days after CCI, but not sham surgery. Systemic administration of the selective HDAC3 antagonist RGFP966 attenuated CCI-induced memory impairment, improved hippocampal long-term potentiation impairment, and rescued reductions of dendritic spine density and synaptic plasticity-associated protein in the hippocampus. In addition, HDAC3 overexpression in the hippocampus led to memory impairment without affecting basal nociceptive responses in naive mice. Our findings suggest that HDAC3 contributes to memory impairment after CCI by impairing synaptic plasticity in hippocampus. Histone deacetylase 3 might serve as a potential molecular target for therapeutic treatment of memory impairment under neuropathic pain conditions.

Disruption of Foxg1 impairs neural plasticity leading to social and cognitive behavioral defects.

The transcription factor Foxg1 is known to be continuously expressed at a high level in mature neurons in the telencephalon, but little is known about its role in neural plasticity. Mutations in human FOXG1 cause deficiencies in learning and memory and limit social ability, which is defined as FOXG1 syndrome, but its pathogenic mechanism remains unclear. To examine the role of Foxg1 in adults, we crossed Camk2a-CreER with Foxg1fl/fl mice and conditionally disrupted Foxg1 with tamoxifen in mature neurons. We found that spatial learning and memory were significantly impaired when examined by the Morris water maze test. The cKO mice also showed a significant reduction in freezing time during the contextual and cued fear conditioning test, indicating that fear conditioning memory was affected. A remarkable reduction in Schaffer-collateral long-term potentiation was also recorded. Morphologically, the dendritic arborization and spine densities of hippocampal pyramidal neurons were significantly reduced. Primary cell culture further confirmed altered dendritic complexity after Foxg1 deletion. Our results indicated that Foxg1 plays an important role in maintaining the neural plasticity, which is vital to high-grade function.