Thus, our studies identified a gene ( Gad1)–environment (PS) interaction related to the development of PV-positive interneurons. The vulnerability of GAD67 +/GFP mice to PS was also reflected in their altered corticosterone levels (Uchida et al., 2011). Furthermore, this resulted in the reduced density of parvalbumin (PV)-expressing GABAergic neurons in the medial prefrontal cortex (mPFC) of postnatal GAD67 +/GFP mice, but not of wild type littermates (Uchida et al., 2014). Using these mice, we reported that the application of restraint PS through mother mice suppressed the neurogenesis of GABAergic neurons in the medial ganglionic eminence (MGE) of GAD67 +/GFP embryos. To determine whether PS and GABA reduction may interact and worsen neural development, we previously examined (GAD67-green fluorescent protein (GFP) Knock-In (KI) GAD67 +/GFP) mice, in which one Gad1 gene is replaced with the GFP gene to reduce GABA production by half (Tamamaki et al., 2003 Wang et al., 2009). Dysfunction of GABAergic signaling results in E/I imbalance affecting individual synaptic inputs to a neuron and overall neural circuitry suggest that reduced GABA-mediated signaling might also be a risk factor for psychiatric disorders. During the postnatal period, GABAergic responses undergo a switch from being excitatory to inhibitory. Early in development, GAD67, an isoform of GABA-synthesizing enzymes, is already expressed, and synthesized GABA has an excitatory effect that regulates neuronal migration and maturation (Ben-Ari, 2002 Heng et al., 2007 Wang and Kriegstein, 2009 Wang et al., 2014 Watanabe and Fukuda, 2015). One of the key molecules that regulates E/I balance in the brain is the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Animal model studies have demonstrated that PS significantly alters neural circuit development and may produce behavioral deficits suggestive of psychiatric disorders (Weinstock, 2008) which is regulated by excitatory/inhibitory balance (E/I balance) at synaptic and network levels. Prenatal stress (PS) is a risk factor that can change the trajectory of fetal brain development and have long-term effects on adult brain function, which may result in psychiatric disorders like autism spectrum disorder (ASD), depression and schizophrenia (Bock et al., 2015). This might be one of the causes of the excitatory/inhibitory imbalance in the mPFC of psychiatric patients. Thus, our study suggests that alterations in the ECM mediated by gene-environment interactions might be linked to the enhanced and prolonged GABA action that compensates for the decreased density of PV neurons. In line with eIPSC, spontaneous IPSC (sIPSC) amplitude, frequency and decay tau were altered. Moreover, the decay rate of eIPSCs was also slowed. When assessing the function of interneurons in the mPFC of GAD67 +/GFP mice with PS through evoked inhibitory post-synaptic currents (eIPSCs) in layer V pyramidal neurons, we found that the threshold stimulus intensity for eIPSC events was reduced and that the eIPSC amplitude was increased without changes in the paired-pulse ratio (PPR). None of these changes were detected in GAD67 +/GFP naive mice or wild type (GAD67 +/+) mice with PS, suggesting that both PS and reduced Gad1 gene expression are prerequisites for these changes. We found that both glycosylated α-DG and the mRNA level of Fktn were reduced in GAD67 +/GFP mice with PS. ![]() ![]() ![]() Glycosylation of α-dystroglycan (α-DG) and its putative mediator fukutin (Fktn) in the ECM around inhibitory synapses has also been suggested to contribute to disease development. Consistent with our previous study, we confirmed a decrease in the density of PV neurons in the mPFC of postnatal GAD67 +/GFP mice with PS, which was concurrent with a decrease in density of PV neurons surrounded by perineuronal nets (PNNs), a specialized ECM important for the maturation, synaptic stabilization and plasticity of PV neurons. To elucidate pathophysiological changes in ECM induced by the gene–environment interaction, we examined heterozygous GAD67-GFP (Knock-In KI GAD67 +/GFP) mice subjected to PS from embryonic day 15.0 to 17.5. Decreased expression of extracellular matrix (ECM) glycoproteins has also been reported in patients with these disorders, raising the possibility that ECM abnormalities may play a role in their pathogenesis. Exposure to prenatal stress (PS) and mutations in Gad1, which encodes GABA synthesizing enzyme glutamate decarboxylase (GAD) 67, are the primary risk factors for psychiatric disorders associated with abnormalities in parvalbumin (PV)-positive GABAergic interneurons in the medial prefrontal cortex (mPFC).
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