Abstract
Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In α5(H105R) mutant mice, the expression of the α5 subunit-containing GABAA receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in α5(H105R) mutant mice. These effects were apparent in both genders. Thus, α5 subunit-containing GABAA receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of α5 GABAA receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of α5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.
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References
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM et al. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401: 796–800.
McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR et al. (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alphal subtype. Nat Neurosci 3: 529–530; 3: 1059.
Löw K, Crestani F, Keist R, Benke D, Brunig I, Benson JA et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290: 131–134.
Crestani F, Low K, Keist R, Mandelli M, Mohler H, Rudolph U. (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59: 442–445.
Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L et al. (2002) Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad Sci USA 99: 8980–8985.
Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C et al. (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22: 5572–5580.
Chambers MS, Atack JR, Broughton HB, Collinson N, Cook S, Dawson GR et al. (2003) Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition. J Neurosci 46: 2227–2240.
Hoffman HS, Searle JR (1965) Ascoustic variables in the modification of startle reaction in the rat. J Comp Exp Psych 60: 53–58.
Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156: 234–258.
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156: 117–154.
Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats: reversal by haloperidol. Psychopharmacology 144: 347–354.
Fendt M, Schwienbacher I, Koch M (2000) Amygdaloid N-methyl-D-aspartate and gamma-aminobutyric acid(A) receptors regulate sensorimotor gating in a dopamine-dependent way in rats. Neuroscience 98: 55–60.
Wan FJ, Swerdlow NR (1997) The basolateral amygdala regulates sensorimotor gating of acoustic startle in the rat. Neuroscience 76: 715–724.
Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156: 194–215.
Bast T, Feldon J (2003) Hippocampal modulation of sensorimotor processes. Prog Neurobiol 70: 319–345.
Pouzet B, Feldon J, Veenman CL, Yee BK, Richmond M, Nicholas J et al. (1999) The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition. Behav Neurosci 113: 968–981.
Swerdlow NR, Lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA (1995) Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats. Psychopharmacology (Berl) 122: 27–34.
Le Pen G, Moreau JL (2002) Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risperidone but not by haloperidol. Neuropsychopharmacology 27: 1–11.
Bast T, Zhang WN, Feldon J (2001a) Hyperactivity, decreased startle reactivity, and disrupted prepulse inhibition following disinhibition of the rat ventral hippocampus by the GABA(A) receptor antagonist picrotoxin. Psychopharmacology (Berl) 156: 225–233.
Bast T, Zhang WN, Heidbreder C, Feldon J (2001b) Hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine. Neuroscience 103: 325–335.
Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG et al. (2004) Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA 101: 3662–3667.
Brünig I, Scotti E, Sidler C, Fritschy JM (2002) Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J Comp Neurol 443: 43–55.
Lakso M, Pichel JG, Gorman JR, Sauer B, Okamoto Y, Lee E et al. (1996) Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci USA 93: 5860–5865.
Zhang WN, Bast T, Feldon J (2002) Effects of hippocampal N-methyl-D-aspartate infusion on locomotor activity and prepulse inhibition: differences between the dorsal and ventral hippocampus. Behav Neurosci 116: 72–84.
Paylor R, Hirotsune S, Gambello MJ, Yuva-Paylor L, Crawley JN, Wynshaw-Boris A (1999) Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice. Learn Mem 6: 521–537.
Swerdlow NR, Taaid N, Halim N, Randolph E, Kim YK, Auerbach P (2000) Hippocampal lesions enhance startle gating-disruptive effects of apomorphine in rats: a parametric assessment. Neuroscience 96: 523–536.
Caine SB, Humby T, Robbins TW, Everitt BJ (2001) Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle. Behav Neurosci 115: 880–894.
Yee BK, Russig H, Feldon J (2004a) Apomorphine-induced prepulse inhibition disruption is associated with a paradoxical enhancement of prepulse stimulus reactivity. Neuropsychopharmacology 29: 240–248.
Yee BK, Chang DLT, Feldon J (2004b) The effects of MK801 and PCP on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity. Neuropsychopharmacology, in press [Epub ahead of print, 5 May 2004].
Swerdlow NR, Geyer MA (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 24: 285–301.
Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990a) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology (Berl) 101: 414–420.
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990b) Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology (Berl) 100: 413–416.
Ferguson SA, Paule MG, Holson RR (2001) Neonatal dexamethasone on day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits. Neurotoxicol Teratol 23: 57–69.
Weiss IC, Feldon J (2001) Environmental animal models for sensorimotor gating deficiencies in schizophrenia: a review. Psychopharmacology (Berl) 156: 305–326.
Ouagazzal AM, Jenck F, Moreau JL (2001) Drug-induced potentiation of prepulse inhibition of acoustic startle reflex in mice: a model for detecting antipsychotic activity? Psychopharmacology (Berl) 56: 273–283.
Benes FM (1999) Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry 46: 589–599.
Benes FM, Berretta S (2001) GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25: 1–27.
Sur C, Quirk K, Dewar D, Atack J, McKernan R (1998) Rat and human hippocampal alpha5 subunit-containing gamma-aminobutyric AcidA receptors have alpha5 beta3 gamma2 pharmacological characteristics. Mol Pharmacol 54: 928–933.
Sur C, Fresu L, Howell O, McKernan RM, Atack JR (1999) Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain. Brain Res 822: 265–270.
Acknowledgements
This study was supported by the Swiss Federal Institute of Technology Zurich. BK Yee received additional support from the NCCR: Neural Plasticity and Repair, Swiss National Science Foundation. We thank Mr Peter Schmid for his technical expertise, and Ms Misa Kuper-Yamanaka for her editorial assistance. We remain also indebted to Jeanne von Arx and Pascal Guela for their care of the animals and to Dr Frank Bootz for his veterinary supervision.
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Hauser, J., Rudolph, U., Keist, R. et al. Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition. Mol Psychiatry 10, 201–207 (2005). https://doi.org/10.1038/sj.mp.4001554
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DOI: https://doi.org/10.1038/sj.mp.4001554
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