Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Abstract

Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.

Maternally derived hormones, neurosteroids and the development of behaviour

“…R. Soc. B 288: 20202467 to placental neurosteroids in utero is linked to a greater risk of developing attention deficit hyperactivity disorder, anxiety and other long-term behavioural consequences of pre-term birth [57,60,61]. Together, these findings strongly support the idea that maternally derived neurosteroids influence electrical activity in neurons and are essential for the normal development of neural function and behaviour.…”

“…Action of GABA on these receptors decreases the likelihood of post-synaptic electrical activity in neural circuits. Neurosteroids, including those created from maternal steroid precursors, can increase or decrease the receptor's affinity for GABA, thereby altering the likelihood of action potentials [53,54], neural activity, and may have major implications for the developing nervous system [55][56][57][58][59][60][61][62]. Already, in very early stages of embryonic development, electrical activity is produced by neurons and GABA A receptors are expressed in neurons across tissues [63][64][65][66][67][68].…”

Short-Term Effect of MgSO4 on the Expression of NRG-ErbB, Dopamine, GABA, and Glutamate Systems in the Fetal Rat Brain

“…Moreover, an imbalance between inhibitory and excitatory action can occur if the enzyme responsible for the conversion of glutamate to GABA is affected. In addition, pregnancy challenges are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signaling or alterations in the maturation of inhibitory pathways in the brain, which could lead to behavior disorders (Shaw et al 2020). Our results show a significant impact of MgSO 4 on GAD67 (i.e.…”

“…Studies have shown that GAD67 performs over 90% of basal GABA synthesis in the human and rodent brain (Shaw et al 2020). Once synthesized from glutamate, GABA is then able to act on GABA A receptors to exert trophic and inhibitory action.…”

Neuroactive steroids and the new decade

“…These events could be related to the homeostatic and protective actions of steroids in neural cells, as well as to the manifestation of sex differences in neurodegenerative disorders . The involvement of progesterone in neuroprotection and immunomodulation in Parkinson's disease is described in a mouse model in the study by Jarras et al Other neuroactive steroids are involved in complications of sleep deprivation, in the imbalance of inhibitory and excitatory actions during pregnancy that program for poor behavioural outcomes in a sex‐dependent manner later in life, in some psychiatric diseases such as Tourette's syndrome, and in the regulation of mitochondrial function in tauopathies …”