PT  - JOURNAL ARTICLE
AU  - Benjamin G. Gunn
AU  - Linda Cunningham
AU  - Michelle A. Cooper
AU  - Nicole L. Corteen
AU  - Mohsen Seifi
AU  - Jerome D. Swinny
AU  - Jeremy J. Lambert
AU  - Delia Belelli
TI  - 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
AID  - 10.1523/JNEUROSCI.1337-13.2013
DP  - 2013 Dec 11
TA  - The Journal of Neuroscience
PG  - 19534--19554
VI  - 33
IP  - 50
4099  - http://www.jneurosci.org/content/33/50/19534.short
4100  - http://www.jneurosci.org/content/33/50/19534.full
SO  - J. Neurosci.2013 Dec 11; 33
AB  - 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 (δ0/0) exhibit altered maternal behavior. Intriguingly, δ0/0 offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ0/0 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.