A study on the physiological mechanism to induce neurodevelopmental dysfunction and cognitive decline of pups by prenatal exposure to high cortisol in rats

Abstract

The high level of blood cortisol is one of key factors to identify major depressive disorder as well as attention deficit hyperactivity disorder (ADHD) that may be mediated by the dysregulation of brain-derived neurotrophic factor (BNDF) signaling during brain development. As ADHD is a developmental neuropsychiatric disorder, it is possible that cortisol directly affects the cellular signaling involved in neuronal growth and brain development. However, it remains unclear whether and how elevation in cortisol levels during the prenatal period affects brain functions and induces psychiatric disorders. I have previously reported that rat pups (Corti.Pups) born from rat mothers repetitively injected with corticosterone (20 mg/kg/day) during pregnancy exhibited increased plasma cortisol levels, deficits in spatial cognitive functions, and ADHD-like behaviors during the post-weaning period. In this study, I aimed to investigate the cellular mechanisms underlying cognitive dysfunction caused by neurodevelopmental impairments induced by prenatal exposure to high cortisol levels. For this purpose, I performed behavioral experiments to test learning and memory functions in juvenile rat pups, electrophysiological studies to evaluate synaptic functions and cell physiology studies to measure the expressions of neurodevelopment-associated proteins. Behavioral assessments of juvenile Corti.Pups using the Morris water maze and Open field tests suggested a possibility that their spatial learning and memory functions were neurophysiologically downregulated, compared with normal rat pups (Nor.Pups). In the electrophysiological experiments to test membrane excitability and synaptic plasticity in hippocampal CA1 neurons of Corti.Pups (postnatal 13 ~ 18 days) using acute slice patch clamping, the synaptic responses to generate excitatory postsynaptic currents were remarkably suppressed in Corti.Pups. Furthermore, impairments in synaptic long-term potentiation in CA1 neurons, which is the cellular mechanism to reflect the learning and memory formation, were observed in Corti.Pups. This memory impairment was attributed to the remodeling of synaptic NMDA receptor subunits by the augmentation of synaptic NR2B-mediated responses. These results provide evidence that maternal cortisol imbalances and neuroendocrine dysregulation during pregnancy may directly impair synaptic functions in their pups. Further, enzyme-linked immunosorbent assay revealed a significant reduction in BDNF levels in the prefrontal cortex (PFC) and hippocampus (HPC) of Corti.Pups, compared to that in Nor.Pups. In Western blot experiments, the expression level of PSD-95 was significantly lower in both brain areas of Corti.Pups. Interestingly, mTOR and PKA, which are well-established regulators of BDNF levels, were only less expressed in PFC of Corti.Pups. These results indicate that cortisol potently downregulates developmental signaling in the brain during prenatal and postnatal periods. This suggests that cortisol targets neuroendocrine regulation involving catecholamines, such as dopamine, which is a key factor initiating BDNF-mediated signaling cascades for brain development. Here, I provide experimental evidence demonstrating that compared to Nor.Pups, Corti.Pups exhibit synaptic loss and deficits in hippocampal neurons and those major cellular factors that contribute to neuronal development in the PFC and HPC were significantly less expressed. This study clearly provides evidence that cortisol downregulates synaptic development and functions to be important for learning and memory by triggering neuroendocrine dysregulation during brain development, which may contribute to ADHD pathogenesis.