مقاله انگلیسی رایگان در مورد مکانیسم های داخل سلولی و تغییرات رفتاری در مدل mouse اختلال کم توجهی-بیش فعالی – الزویر 2020

1- Introduction

2- Experimental procedures

3- Results

4- Discussion

5- Conclusion

References

Abstract

Exposure of NMDA receptor antagonists during developmental stages leads to behavioral consequences like attention deficit hyperactivity disorder (ADHD). However, the underlying molecular mechanisms have remained poorly understood. Herein, we studied the phosphorylated Akt (pAkt) and caspase-3, the key regulators of neuronal cell survival/death, as the probable downstream targets of MK-801 often used to engender ADHD-like condition. Swiss albino mice at postnatal days (PND) 7, 14 or 21 were injected with a single dose of MK-801 and evaluated for hyperactivity (open field test) and memory deficit at adolescence (PND 30) and adult stages (PND 60). PND 7 or 14 treatment groups (but not PND 21) consistently showed hyperactivity at the adolescence stage. A significant increase in working and reference memory errors in radial arm maze was noted at the adolescence age. PND 7 group continued to display the symptoms even in adulthood. All the treatment groups showed a significant decrease in the percent alterations (Y-maze) and discrimination index (novel object recognition test) at adolescence age. A significant increase in caspase-3 expression was noted in the prefrontal cortex (PFC) and hippocampus, whereas increased pAkt was noticed only in the hippocampus, following a single injection of MK-801 at PND 7. Concurrently, PND 7 treatment group showed significantly decreased neuronal nuclei (NeuN) expression (a marker for mature neurons) in the dentate gyrus, cornu ammonis-3 and PFC, but not in cornu ammonis-1, at adolescence age. We suggest that the observed symptoms of ADHD at adolescence and adulthood stages may be linked to alteration in pAkt and caspase-3 followed MK-801 treatment at PND 7.

Introduction

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impaired attention and impulsiveness (Sroubek et al., 2013). Individuals with ADHD also show poor working memory and executive function (Holmes et al., 2014). ADHD is highly prevalent during childhood and frequently persists into adulthood (Kooij et al., 2010). It affects approximately 5–10% of children worldwide (Willcutt, 2012). Several studies correlate dysregulation in the neurotransmission of dopamine, norepinephrine, glutamate and serotonin systems with the appearance of ADHD symptoms (Russell, 2002; Sagvolden et al., 2005; Feldman and Reiff, 2014). Imaging studies showed the involvement of frontal-motor cortex circuitry in ADHD patients (Giedd et al., 2001; Clark et al., 2007). Previous reports indicate an involvement of multiple genetic factors as the etiological basis of ADHD, however, exposure to various environmental agents during neuronal development have been suggested as causal factors (Brondum, 2007; Faraone and Larsson, 2019). It is also reveal that ADHD is not a single pathophysiological entity, but involves multiple interacting factors (Faraone et al., 2015). Exposure to various pharmacological agents (ethanol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane and propofol) during synaptogenesis triggers apoptosis throughout the brain and leads to psychiatric disorders later in life (Ikonomidou et al., 1999; Olney et al., 2000). Largely synaptogenesis and other constructive anatomical developments occur during the first three weeks in the life of rodents.