Neurosteroids involved in regulating inhibition in the inferior colliculus.

Fast inhibitory neurotransmission in the brain is largely mediated by the gamma-aminobutyric acid-type A (GABA(A)) receptor. The 3alpha,5alpha-reduced neurosteroids (e.g., allopregnanolone) are the most potent endogenous modulators of the GABA(A) receptor. Although it is known that 3alpha,5alpha-reduced neurosteroid levels change during stress or depression and over the estrus cycle, a basic physiological role consistent with their pharmacological action remains elusive. We used the unique architecture of the auditory midbrain to reveal a role for 3alpha,5alpha-reduced neurosteroids in regulating inhibitory efficacy. After blocking the massive GABAergic projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the contralateral central nucleus of the inferior colliculus (ICC) in anesthetized rats, a reactive increase in the efficacy of other inhibitory circuits in the ICC (separable because of the dominant ear that drives each circuit) was demonstrated with physiological measures-single-neuron activity and a neural-population-evoked response. This effect was prevented by blocking 3alpha,5alpha-reduced neurosteroid synthesis with a 5alpha-reductase inhibitor: finasteride. Immunohistochemistry confirmed that the DNLL blockade induced an increase in 3alpha,5alpha-reduced neurosteroids in the contralateral ICC. This study shows that when GABAergic inhibition is reduced, the brain compensates within minutes by locally increasing synthesis of neurosteroids, thereby balancing excitatory and inhibitory inputs in complex neural circuits.

[1]  T. Penning,et al.  Anatomical and cellular localization of neuroactive 5α/3α‐reduced steroid‐synthesizing enzymes in the spinal cord , 2004 .

[2]  C. Zorumski,et al.  Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors. , 2004, Molecular pharmacology.

[3]  K. Tsutsui,et al.  Cellular distribution and bioactivity of the key steroidogenic enzyme, cytochrome P450side chain cleavage, in sensory neural pathways , 2003, Journal of neurochemistry.

[4]  S. Moss,et al.  Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition , 2003, Current Opinion in Neurobiology.

[5]  V. Lingappa,et al.  Rapid regulation of steroidogenesis by mitochondrial protein import , 2002, Nature.

[6]  M. Rogawski,et al.  Stress-Induced Deoxycorticosterone-Derived Neurosteroids Modulate GABAA Receptor Function and Seizure Susceptibility , 2002, The Journal of Neuroscience.

[7]  B. Stoffel‐Wagner Neurosteroid metabolism in the human brain. , 2001, European journal of endocrinology.

[8]  C. Frye,et al.  Ventral Tegmental Area Infusions of Inhibitors of the Biosynthesis and Metabolism of 3α,5α‐THP Attenuate Lordosis of Hormone‐Primed and Behavioural Oestrous Rats and Hamsters , 2001, Journal of neuroendocrinology.

[9]  F. Camargo,et al.  Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. , 2001, Life sciences.

[10]  M. Tschöp,et al.  Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. , 2001, European journal of endocrinology.

[11]  B. Frenguelli,et al.  Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids , 2001, Brain Research Reviews.

[12]  A. Disney,et al.  Neurosteroids mediate habituation and tonic inhibition in the auditory midbrain. , 2001, Journal of neurophysiology.

[13]  T. Tsurugizawa,et al.  Neurosteroid synthesis by cytochrome p450-containing systems localized in the rat brain hippocampal neurons: N-methyl-D-aspartate and calcium-dependent synthesis. , 2001, Endocrinology.

[14]  D. A. Godfrey,et al.  Amino acid concentrations in rat cochlear nucleus and superior olive , 2000, Hearing Research.

[15]  G. Sperk,et al.  GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain , 2000, Neuroscience.

[16]  S. Wu,et al.  Long-term potentiation in the inferior colliculus studied in rat brain slice , 2000, Hearing Research.

[17]  T. Sugawara,et al.  Sp1 and SF-1 interact and cooperate in the regulation of human steroidogenic acute regulatory protein gene expression. , 2000, Endocrinology.

[18]  D. B. Matthews,et al.  Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol , 2000, The Journal of Neuroscience.

[19]  F. Holsboer,et al.  Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives , 1999, Trends in Neurosciences.

[20]  J. Schramm,et al.  Characterization of aromatase cytochrome P450 activity in the human temporal lobe. , 1999, The Journal of clinical endocrinology and metabolism.

[21]  Mark J. West,et al.  Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias , 1999, Trends in Neurosciences.

[22]  G. Biggio,et al.  Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Peter Somogyi,et al.  Increased number of synaptic GABAA receptors underlies potentiation at hippocampal inhibitory synapses , 1998, Nature.

[24]  V. Kotak,et al.  A Developmental Shift from GABAergic to Glycinergic Transmission in the Central Auditory System , 1998, The Journal of Neuroscience.

[25]  C. Cascio,et al.  Induction of neurosteroid synthesis by NMDA receptors in isolated rat retina: a potential early event in excitotoxicity , 1998, The European journal of neuroscience.

[26]  A. Guidotti,et al.  Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  F. Petraglia,et al.  Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats. , 1998, European journal of endocrinology.

[28]  J. Kelly,et al.  GABAergic projections from the lateral lemniscus to the inferior colliculus of the rat , 1998, Hearing Research.

[29]  H. Watari,et al.  Phosphorylation of Steroidogenic Acute Regulatory Protein (StAR) Modulates Its Steroidogenic Activity* , 1997, The Journal of Biological Chemistry.

[30]  J E Mossop,et al.  Response properties of neurons in the inferior colliculus of the monaurally deafened ferret to acoustic stimulation of the intact ear. , 1997, Journal of neurophysiology.

[31]  H. Bull,et al.  Inhibition of rat α-reductases by finasteride: Evidence for isozyme differences in the mechanism of inhibition , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  P. Bertics,et al.  Regional distribution of cytosolic and particulate 5α-dihydroprogesterone 3α-hydroxysteroid oxidoreductases in female rat brain , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[33]  H. Pérez-González,et al.  Sources of GABAergic input to the inferior colliculus of the rat , 1996, The Journal of comparative neurology.

[34]  A. Møller,et al.  Effects of (−)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: possible therapeutic implications for pharmacological management of tinnitus and hyperacusis , 1996, Hearing Research.

[35]  F. Petraglia,et al.  Allopregnanolone concentration in hippocampus of prepubertal rats and female rats throughout estrous cycle , 1995, Journal of endocrinological investigation.

[36]  H. Hirai,et al.  Long-term potentiation of neurotransmission in the inferior colliculus of the rat , 1995, Neuroscience Letters.

[37]  A. Guidotti,et al.  Gas chromatographic-mass fragmentographic quantitation of 3 alpha- hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  K. Gee,et al.  Potency of lipid and protein formulation of 5 alpha-pregnanolone at induction of anaesthesia and the corresponding regional brain distribution. , 1995, British journal of anaesthesia.

[39]  M. Trabucchi,et al.  Modulatory mechanisms of cyclic AMP-stimulated steroid content in rat brain cortex. , 1994, European journal of pharmacology.

[40]  V. Papadopoulos,et al.  Neurosteroidogenesis in Rat Retinas , 1994, Journal of neurochemistry.

[41]  A. Guidotti,et al.  Regionaland Interspecies Differences in Brain Progesterone Metabolism , 1993, Journal of neurochemistry.

[42]  J. Sjövall,et al.  Neurosteroids: 3 alpha-hydroxy-5 alpha-pregnan-20-one and its precursors in the brain, plasma, and steroidogenic glands of male and female rats. , 1993, Endocrinology.

[43]  L. Li,et al.  Inhibitory influence of the dorsal nucleus of the lateral lemniscus on binaural responses in the rat's inferior colliculus , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[44]  M. Trabucchi,et al.  Cyclic AMP-dependent increase of steroidogenesis in brain cortical minces. , 1992, European journal of pharmacology.

[45]  P. H. Moore,et al.  Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Caspary,et al.  Involvement of GABA in acoustically-evoked inhibition in inferior colliculus neurons , 1991, Hearing Research.

[47]  B Sakmann,et al.  Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch‐clamp study. , 1990, The Journal of physiology.

[48]  E. Baulieu,et al.  Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. , 1989, Endocrinology.

[49]  G. Scala,et al.  Effects of unilateral microinjections of gabaergic drugs into the inferior colliculus on auditory evoked potentials and on audiogenic seizure susceptibility , 1989, Experimental Neurology.

[50]  P. Rakic,et al.  Three‐dimensional counting: An accurate and direct method to estimate numbers of cells in sectioned material , 1988, The Journal of comparative neurology.

[51]  R. Roberts,et al.  An electron microscopic study of GABAergic neurons and terminals in the central nucleus of the inferior colliculus of the rat , 1987, Journal of neurocytology.

[52]  S. Paul,et al.  Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. , 1986, Science.

[53]  M. Semple,et al.  Single-unit responses in the inferior colliculus: effects of neonatal unilateral cochlear ablation. , 1985, Journal of neurophysiology.

[54]  K. Osen,et al.  Anatomy of the inferior colliculus in rat , 2004, Anatomy and Embryology.

[55]  B. Grothe,et al.  The functional role of GABA and glycine in monaural and binaural processing in the inferior colliculus of horseshoe bats , 2004, Journal of Comparative Physiology A.

[56]  B. Barisas,et al.  Steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor associate at the mitochondrial membrane. , 2001, Endocrinology.

[57]  D. B. Matthews,et al.  Neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[58]  P. Bertics,et al.  Regional distribution of cytosolic and particulate 5alpha-dihydroprogesterone 3alpha-hydroxysteroid oxidoreductases in female rat brain. , 1997, The Journal of steroid biochemistry and molecular biology.

[59]  D. Irvine The Auditory Midbrain: Anatomy and Physiology , 1986 .

[60]  D. Irvine The Auditory Brainstem , 1986, Progress in Sensory Physiology.