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Br J Pharmacol
2018 Jun 01;17512:2414-2427. doi: 10.1111/bph.14198.
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Cerebellar α6 -subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.
Chiou LC
,
Lee HJ
,
Ernst M
,
Huang WJ
,
Chou JF
,
Chen HL
,
Mouri A
,
Chen LC
,
Treven M
,
Mamiya T
,
Fan PC
,
Knutson DE
,
Witzigmann C
,
Cook J
,
Sieghart W
,
Nabeshima T
.
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BACKGROUND AND PURPOSE: The pathophysiological role of α6 -subunit-containing GABAA receptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar α6 GABAA receptors. Here, using hispidulin and a selective α6 GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6 GABAA receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders.
EXPERIMENTAL APPROACH: PPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant α6 β3 γ2S GABAA receptors.
KEY RESULTS: Hispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two α6 GABAA receptor PAMs), but not by diazepam (an α6 GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an α6 GABAA receptor antagonist. Importantly, Compound 6 (i.p.) also rescued methamphetamine-induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound 6 potentiated α6 β3 γ2S GABAA receptor-mediated GABA currents.
CONCLUSIONS AND IMPLICATIONS: Positive allosteric modulation of cerebellar α6 GABAA receptors rescued disrupted PPI by attenuating granule cell activity. α6 GABAA receptor-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating.
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Voltage-gated ion channels.
2017, Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Voltage-gated ion channels.
2017,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes.
2017,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-gated ion channels.
2017,
Pubmed
Andreasen,
Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.
1996,
Pubmed
Braff,
Prestimulus effects on human startle reflex in normals and schizophrenics.
1978,
Pubmed
Bullock,
Altered expression of genes involved in GABAergic transmission and neuromodulation of granule cell activity in the cerebellum of schizophrenia patients.
2008,
Pubmed
Caligiore,
Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex.
2017,
Pubmed
Chen,
Clerodendrum inerme Leaf Extract Alleviates Animal Behaviors, Hyperlocomotion, and Prepulse Inhibition Disruptions, Mimicking Tourette Syndrome and Schizophrenia.
2012,
Pubmed
Chiou,
Cerebellar α<sub>6</sub> -subunit-containing GABA<sub>A</sub> receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders.
2018,
Pubmed
,
Xenbase
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
Derry,
Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding.
2004,
Pubmed
Ellenbroek,
Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex.
1996,
Pubmed
Fan,
Intractable chronic motor tics dramatically respond to Clerodendrum inerme (L) Gaertn.
2009,
Pubmed
Farrell,
COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.
2012,
Pubmed
Freitag,
Neurophysiology of nocturnal enuresis: evoked potentials and prepulse inhibition of the startle reflex.
2006,
Pubmed
Giakoumaki,
Evidence of disrupted prepulse inhibition in unaffected siblings of bipolar disorder patients.
2007,
Pubmed
Grayson,
Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review.
2016,
Pubmed
Gutiérrez,
Immunocytochemical localization of the alpha 6 subunit of the gamma-aminobutyric acidA receptor in the rat nervous system.
1996,
Pubmed
Hadingham,
Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.
1996,
Pubmed
,
Xenbase
Harding,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY.
2018,
Pubmed
Huang,
Hispidulin, a constituent of Clerodendrum inerme that remitted motor tics, alleviated methamphetamine-induced hyperlocomotion without motor impairment in mice.
2015,
Pubmed
Kask,
Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle.
2008,
Pubmed
Kavvadias,
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects.
2004,
Pubmed
,
Xenbase
Kavvadias,
Constituents of sage (Salvia officinalis) with in vitro affinity to human brain benzodiazepine receptor.
2003,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Knoflach,
Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2.
1996,
Pubmed
Koch,
Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol.
1994,
Pubmed
Korpi,
Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor.
1995,
Pubmed
,
Xenbase
Kumari,
Association between violent behaviour and impaired prepulse inhibition of the startle response in antisocial personality disorder and schizophrenia.
2005,
Pubmed
Leckman,
Premonitory urges in Tourette's syndrome.
1993,
Pubmed
Lewis,
Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction.
2004,
Pubmed
Liao,
Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6 subunit-containing GABAA receptors in the cerebellum.
2016,
Pubmed
Ludewig,
Prepulse inhibition deficits in patients with panic disorder.
2002,
Pubmed
MADDOX,
THE SYNTHESIS OF PHENCYCLIDINE AND OTHER 1-ARYLCYCLOHEXYLAMINES.
1965,
Pubmed
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Minier,
Positioning of the alpha-subunit isoforms confers a functional signature to gamma-aminobutyric acid type A receptors.
2004,
Pubmed
,
Xenbase
Mirheydari,
Unexpected Properties of δ-Containing GABAA Receptors in Response to Ligands Interacting with the α+ β- Site.
2014,
Pubmed
,
Xenbase
Mittleman,
Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia.
2008,
Pubmed
Mothersill,
Emotion and Theory of Mind in Schizophrenia-Investigating the Role of the Cerebellum.
2016,
Pubmed
Najac,
Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons.
2015,
Pubmed
Nelson,
Reassessing models of basal ganglia function and dysfunction.
2014,
Pubmed
Nieus,
Regulation of output spike patterns by phasic inhibition in cerebellar granule cells.
2014,
Pubmed
Nissinen,
Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat.
1988,
Pubmed
Nusser,
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells.
1998,
Pubmed
Ornitz,
Prestimulation-induced startle modulation in attention-deficit hyperactivity disorder and nocturnal enuresis.
1992,
Pubmed
Person,
Synchrony and neural coding in cerebellar circuits.
2012,
Pubmed
Phillips,
The cerebellum and psychiatric disorders.
2015,
Pubmed
Pirker,
GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.
2000,
Pubmed
Pugh,
Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei.
2009,
Pubmed
Sacchetti,
The cerebellum: synaptic changes and fear conditioning.
2005,
Pubmed
Sagud,
Catechol-O-methyl transferase and schizophrenia.
2010,
Pubmed
Singer,
Tourette's syndrome: from behaviour to biology.
2005,
Pubmed
Swerdlow,
Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration.
2007,
Pubmed
Swerdlow,
Tactile prepuff inhibition of startle in children with Tourette's syndrome: in search of an "fMRI-friendly" startle paradigm.
2001,
Pubmed
Swerdlow,
A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder.
1993,
Pubmed
Swerdlow,
Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains.
2013,
Pubmed
Swerdlow,
Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease.
1995,
Pubmed
Takeuchi,
Roles of the glutamate receptor epsilon2 and delta2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex.
2001,
Pubmed
Tunbridge,
Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond.
2006,
Pubmed
Varagic,
Subtype selectivity of α+β- site ligands of GABAA receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors.
2013,
Pubmed
,
Xenbase
Wingrove,
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
1994,
Pubmed
,
Xenbase
Zhang,
Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors.
1995,
Pubmed
Zou,
Low dose MK-801 reduces social investigation in mice.
2008,
Pubmed
