title: Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABA(A) receptor δ subunit in cerebellar granule neurons and delays motor development in rats.
abstract: Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3rd trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 h of exposure. EtOH levels gradually decreased to baseline 8 h after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABA(A) receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats.
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Marvin R
authors: MR
authors: Diaz
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Cyndel C
authors: CC
authors: Vollmer
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Paula A
authors: PA
authors: Zamudio-Bulcock
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: William
authors: W
authors: Vollmer
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Samantha L
authors: SL
authors: Blomquist
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Russell A
authors: RA
authors: Morton
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: Julie C
authors: JC
authors: Everett
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Agnieszka A
authors: AA
authors: Zurek
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Jieying
authors: J
authors: Yu
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors: Beverley A
authors: BA
authors: Orser
authors: Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. Electronic address: fvalenzuela@salud.unm.edu.
authors: C Fernando
authors: CF
authors: Valenzuela
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity*; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000503:physiopathology; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D007555:Isoxazoles; D011963:Receptors, GABA-A; D000431:Ethanol; C015542:gaboxadol
keywords: Cerebellum; Ethanol; Extrasynaptic; Fetal; GABA; Tonic current