Brief Alteration of NMDA or GABAA Receptor-mediated Neurotransmission Has Long Term Effects on the Developing Cerebral Cortex

Abstract

Neurotransmitter signaling is essential for physiologic brain development. Sedative and anticonvulsant agents that reduce neuronal excitability via antagonism at Nmethyl-D-aspartate receptors (NMDARs) and/or agonism at ␥-aminobutyric acid subtype A receptors (GABA A Rs) are applied frequently in obstetric and pediatric medicine. We demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABA A R agonist phenobarbital not only has acute but also long term effects on the cerebral cortex. Changes of the cerebral cortex proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6 suggest that a suppression of synaptic neurotransmission during brain development dysregulates proteins associated with apoptosis, oxidative stress, inflammation, cell proliferation, and neuronal circuit formation. These effects appear to be age-dependent as most protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Previously performed histological evaluations of the brains revealed widespread apoptosis and decreased cell proliferation following such a drug treatment in infancy and are thus consistent with brain protein changes reported in this study. Our results point toward several pathways modulated by a reduction of neuronal excitability that might interfere with critical developmental events and thus affirm concerns about the impact of NMDAR-and/or GABA A

Developmental Expression and Distribution of GABA_A Receptor α₁-, α₃- and β₂-Subunits in Pig Brain

“…Furthermore, although the pharmacological properties of GABA A receptors in the immature brain are similar to the adult, the developmental differences in GABA A receptor structure and function may have significant implications for the management of seizures and injury in the neonatal brain. Exposure to widely used anticonvulsants such as phenobarbital during critical periods of brain development have been shown to result in disturbances in a number of neurotransmitter systems as well as increased levels of apoptosis [54]. …”

GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice

“…Besides the reductions in neuronal number, early exposure to muscimol or to MK801 has several other actions that disrupt the normal sequence of events involved in the formation of brain connections that may lead to dysfunctional corticostriatal and corticocerebellar circuits observed in ADHD (Arnsten, 2011;Durston et al, 2011;Liston et al, 2011). For instance, the blockade of NMDAR or the overactivation of GABAAR in immature neurons, even at concentrations that are too low to induce apoptosis, impairs neuronal differentiation and reduces synapse integrity (Sinner et al, 2011a,b); dysregulates several proteins involved in neuronal migration, axon growth and guidance (Kaindl et al, 2008) and promotes alterations in lamination and heterotopic cell clusters (Heck et al, 2007;Reiprich et al, 2005) in the rodent cerebral cortex. Most of these effects have been directly or indirectly associated with an increase in locomotor activity (Casanova, 2014;Drerup et al, 2010;Komada et al, 2014;Shin et al, 2004).…”

“…Both the blockade of NMDAR and the overactivation of GABAAR during the brain growth spurt trigger widespread apoptotic neurodegeneration (Ikonomidou, 2009), reduce neurogenesis and cell proliferation in the infant rodent brain (Stefovska et al, 2008) and promote acute and long-lasting dysregulation in proteins associated with cell proliferation and neuronal circuit formation, effects that may have a central role in generating the hyperactive phenotype (Kaindl et al, 2008). Interestingly, NMDA antagonists and GABA agonists produce their own distinct brain damage pattern (Ikonomidou et al, , 2001, probably due to marked differences between NMDAR and GABAAR regarding their spatiotemporal distribution during development.…”

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

“…Interestingly, microglial thin processes express several classes of neurotransmitter receptors and ion channels, normally found in neurons [3]. It has been demonstrated that NMDA receptors expressed by microglia can modulate the neuroinflammatory process, influencing reactive oxygen species (ROS) and cytokines production [62]. This rich equipment in neurotransmitter receptors and ion channels could be useful in physiological conditions to sample the extracellular matrix, monitoring neuronal activity near microglial cells.…”