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 the postnatal period, there were dramatic increases in the expression of myelin-related genes and the parvalbumin gene, peaking at postnatal day (P)21 and P35, respectively. The timing of the peaks is different from that observed in the striatum. Furthermore, the evaluation of the circuitry maturation by measuring extracellular glutamate in the PFC revealed that sensitivity to an NMDA antagonist did not become an adult-like pattern till P56, suggesting that some of the maturation processes continue till P56. The trajectory of molecular events in PFC maturation described here should help us to characterize how the processes are affected in disease model mice, an important first step for translational research.

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

“…We have begun to clarify these by characterizing a sequence of gene expression patterns during mouse PFC development (Ueda et al, 2015, and Figure 3). The study showed that the developmental processes of PFC proceed sequentially, and interneuron maturation and myelination take place relatively later in the maturation (by postnatal day 35), supporting the idea that myelination is correlated with local circuitry maturation.…”

“…The study showed that the developmental processes of PFC proceed sequentially, and interneuron maturation and myelination take place relatively later in the maturation (by postnatal day 35), supporting the idea that myelination is correlated with local circuitry maturation. But even after postnatal day 35, the circuitry is still immature and continues to further maturate during adolescence (based on the responsiveness to MK801 injection measured by microdialysis, at postnatal day 42, the PFC does not show the adult like response which is observed at postnatal day 56)(Ueda et al, 2015). The maturation of PFC circuitry is slower than in any other brain regions (e.g., Teffer et al, 2013; Ueda et al, 2015).…”

“…But even after postnatal day 35, the circuitry is still immature and continues to further maturate during adolescence (based on the responsiveness to MK801 injection measured by microdialysis, at postnatal day 42, the PFC does not show the adult like response which is observed at postnatal day 56)(Ueda et al, 2015). The maturation of PFC circuitry is slower than in any other brain regions (e.g., Teffer et al, 2013; Ueda et al, 2015). Even so, the window of plasticity during PFC development (critical period) eventually closes due to various mechanisms (Ko et al, 2013; Woo, 2014), e.g., the appearance of perineural nets comprised of chondroitin sulfate proteoglycans, nogo receptor/myelin inhibitors, and lynx proteins (Nabel and Morishita, 2013).…”

“…The duration of plasticity of the circuitry may determine the time period susceptible to various insults during development (Figure 3). Interestingly, social isolation, an environmental insult, during the early phase of development affects myelination, whereas social isolation during the late phase affects the dopamine system, reflecting the timing of specific biological processes taking place (Makinodan et al, 2012; Niwa et al, 2013; Ueda et al, 2015, Figure 3). In primates, development of glutamatergic and GABAergic circuits has been studied, and sensitive periods for vulnerability to schizophrenia have been mapped as well (Hashimoto et al, 2009; Hoftman and Lewis, 2011).…”

“…Social isolation, an environmental insult, performed during postnatal week 3–5 affects myelin formation, whereas that performed during postnatal week 5–8 affects dopamine synthesis via stress response. Interestingly, the different timing of the treatment results in different behavioral phenotypes later in life (Makinodan et al, 2012; Niwa et al, 2013; Ueda et al, 2015). …”