• A survey of the behavioral and neurobiological effects of prenatal stress on the GABA and Glutamate system
  • Melika Noori,1 Dr. Ehsan Saboory,2,*
    1. Student of surgical technology, Department of Surgical technology, Nursing and Midwifery school, Zanjan University of Medical Sciences, Zanjan, Iran
    2. Department of Addiction studies, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran


  • Introduction: Prenatal stress (PS) is defined as the stress experienced by a mother before giving birth. PS can cause early and long-lasting effects on neurobehavioral development in both human and animal offspring and results in dysregulation of the major inhibitory (GABAergic) and excitatory (glutamatergic) systems in the CNS. A correct balance of activity of the GABA and glutamate systems is essential for neurodevelopment and CNS function. Dysregulation of this balance has been implicated in several neurological and/or psychiatric disorders. This study aims to highlight the new findings on some of the underlying mechanisms of GABA and Glutamate system dysregulation by PS, and the behavioral consequences.
  • Methods: The available literature in “PubMed”, “Google Scholar” and “ScienceDirect” databases was analyzed using the keywords prenatal stress, Glutamate, neurobiology, behavior, and the results with scientific evidence for behavioral and neurobiological effects of prenatal stress on GABA and Glutamate system were summarized.
  • Results: Alterations of the GABAergic and/or glutamatergic signaling during fetal development lead to a severe excitatory/inhibitory imbalance, a condition that may account for PS-precipitated anxiety-like behaviors. The hippocampus, frontal cortex, and amygdala are PS’s most affected brain regions. The amygdala plays an important role in the regulation of emotions and is inhibited by GABAergic neurotransmission, which prevents improper emotional and behavioral responses. PS has been demonstrated to affect the amygdala’s GABAergic neurons. Exposure to PS for a long time leads to the hippocampus's long-lasting dysfunction, which may continue to adulthood. Maternally stressed rats had increased anxiety-like behavior in adulthood, associated with altered expression of the α1, α2, β1–3, and γ2 subunits of the GABA receptor. Thus, we can conclude that PS may increase anxiety-related behaviors. Hippocampus is one of the brain regions responsible for memory stabilization. PS impairs memory function by leading to dysfunction of GABA in the hippocampus, and has been demonstrated to be one of the reasons for the seizure; PS can release stress hormones by the mother’s endocrine system. These hormones cause a significant elevation in the density of NMDA receptors in different brain regions, including the hippocampus. GABA receptors consist of three groups of receptors (A, B, and C); the GABAA receptor is mainly involved in the regulation of neural excitability, anxiety, learning, and memory. Genetic alterations in this receptor have a role in some psychiatric or/and neurological disorders like epilepsy, depression, autism, and schizophrenia. PS increases the α5 subunit of the GABAA receptor in infant rats' hippocampus. The expression of the GABAA receptor δ subunit increases in patients with epilepsy. This subunit's function is as same as the α5 subunit's function but in dentate gyrus granule cells. Therefore, the alterations in the GABAergic system in certain brain structures such as the hippocampus mediate some aspects of PS-induced potentiation in seizure. Recent studies indicate that an imbalance between GABA and glutamate neurotransmission can be a significant mechanism underlying schizophrenia pathophysiology. Adult offspring of prenatal restraint stressed (PRS) mice, exhibit a deficiency in cortical GABAergic innervation. This is expected to result in aberrant synchronization of the firing rate of pyramidal neurons, a putative electrophysiological substrate of cognitive dysfunction in psychotic disorders. They show molecular disruption in chromatin remodeling at genes expressed in glutamatergic neurons, such as mGlu2/3 receptors, and exhibit a schizophrenia-like behavioral phenotype as well. These molecular alternations in PRS mice are alike those observed in the brain of schizophrenia patients, indicating a powerful correlation between schizophrenia symptoms and the altered epigenetic GABAergic/glutamatergic mechanisms. PS is a remarkable risk factor for the development of schizophrenia in the adult offspring of humans.
  • Conclusion: Prenatal stress, altering the GABA and Glutamate system mechanisms, causes many diverse neurological/psychiatric disorders such as behavioral abnormalities, anxiety, decreased learning and memory ability, epilepsy, seizure, schizophrenia, and some other disorders like autism, ADHD, major depression, bipolar disorder, infantile spasms, and even development of addictive states, which are beyond the scope of this paper. Therefore, pharmacological and psychotherapeutic interventions with regulatory effects on the excitatory/inhibitory balance can be attributed to the novel therapeutic target for PS-precipitated disorders.
  • Keywords: prenatal stress, GABA, Glutamate, neurobiology, behavior