Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex

Abstract

Recent progress in psychiatric research has accumulated many mouse models relevant to developmental neuropsychiatric disorders using numerous genetic and environmental manipulations. Since the prefrontal cortex (PFC) is essential for cognitive functions whose impairments are central symptoms associated with the disorders in humans, it has become crucial to clarify altered developmental processes of PFC circuits in these mice. To that end, we aimed to understand a sequence of molecular events during normal mouse PFC development. Expression profiles for representative genes covering diverse biological processes showed that while there were little changes in genes for neuroreceptors and synaptic molecules during postnatal period, there were dramatic increases in expression of myelin-related genes and parvalbumin gene, peaking at postnatal day (P) 21 and P35, respectively. The timing of the peaks is different from one observed in the striatum. Furthermore, evaluation of the circuitry maturation by measuring extracellular glutamate in PFC revealed that sensitivity to an NMDA antagonist became adult-like pattern at P56, suggesting that some of maturation processes continue till P56. The trajectory of molecular events in the PFC maturation described here should help us to characterize how the processes are affected in model mice, an important first step for translational research.

Keywords: dopamine; glutamate; inhibitory neurons; myelination; qRT-PCR; synapse.

Fig. 1

Gene expression profiles in the developing PFC. a AMPARs, b NMDARs, c DRDs, d PSD molecules, e CAMs, f interneuron-related genes, and g oligodendrocyte/myelin-related genes (see table 1). The endogenous control gene, Gapdh, was used for normalization. Data are the means of three independent samples for each point.

Fig. 2

Appearance of PV-positive cells in the developing PFC. The total number of GFP-positive (GFP+) cells in layer 2/3 (a) and layer 5/6 (b) of the anterior cingulate cortex (area 24) of PV/myrGFP-LDLRct mice that express GFP under the PV gene promoter were counted as described in Materials and Methods. Data are the means ± SEM of two independent samples for each point.

Fig. 3

Measurement of extracellular glutamate in the frontal cortex. The changes in the extracellular glutamate level after the administration of MK-801 were monitored by in vivo microdialysis. Data are means ± SEM (n = 10-14 for each group). Statistical significance was determined using one-way ANOVA and subsequent Fisher's PLSD for multiple comparisons. ** p < 0.01.

Fig. 4

Gene expression profiles in the developing striatum. a AMPARs, b NMDARs, c DRDs, d PSD molecules, e CAMs, f interneuron-related genes, and g oligodendrocyte/myelin-related genes (see table 1). The endogenous control gene, Gapdh, was used for normalization. Data are the means of three independent samples for each point.