RESUMO
Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+ transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.
Assuntos
Córtex Pré-Frontal/metabolismo , Fator de Transcrição 4/metabolismo , Fator de Transcrição 4/fisiologia , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/patologia , Neurônios/metabolismo , Córtex Pré-Frontal/embriologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMO
Data from four vendors indicated that purchasing from a prime vendor decreased food cost by 2.5%, as compared with the line-item bidding system. However, the range for prime vendor purchasing was from 2.5% lower than line-item bidding to 8% higher. Thus, if a thorough evaluation of purchasing systems is not conducted, prime vendor purchasing could increase food costs. Purchasing from a prime vendor also reduces administrative and inventory costs and improves the quality and consistency of food purchased. There is a need for thorough evaluation and documentation of purchasing systems. The effectiveness of a purchasing system is measured by its ability to reduce cost while adhering to established guidelines. This article has presented general information obtained from a comparison between line-item and prime vendor bidding for a 104-bed hospital in Georgia.