title: Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response.
abstract: Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ(0/0)) exhibit altered maternal behavior. Intriguingly, δ(0/0) offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ(0/0) pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry.
authors: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom, and Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, United Kingdom.
authors: Benjamin G
authors: BG
authors: Gunn
authors: Linda
authors: L
authors: Cunningham
authors: Michelle A
authors: MA
authors: Cooper
authors: Nicole L
authors: NL
authors: Corteen
authors: Mohsen
authors: M
authors: Seifi
authors: Jerome D
authors: JD
authors: Swinny
authors: Jeremy J
authors: JJ
authors: Lambert
authors: Delia
authors: D
authors: Belelli
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004195:Disease Models, Animal; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D003346:Corticotropin-Releasing Hormone
keywords: GABAA receptors; PVN; allopregnanolone; glutamate transporter; maternal case; stress