Excitation of Rat Cerebellar Golgi Cells by Ethanol: Further Characterization of the Mechanism

Botta, Paolo; Souza, Fábio M. Simões de; Sangrey, Thomas; Schutter, Erik De; Valenzuela, C. Fernando

doi:10.1111/j.1530-0277.2011.01658.x

Cited by 18 publications

(29 citation statements)

References 62 publications

(111 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Instead, when EtOH does affect NHP GC GABA A R transmission it is via excitation of Golgi cells and consequent increased vesicular release of GABA, similar to what has been reported for SDRs (Carta et al, 2004; Botta et al, 2007a,b, 2010, 2012). …”

Section: Discussionsupporting

confidence: 72%

Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype

Mohr

Kolotushkina

Kaplan

et al. 2013

Front. Neural Circuits

View full text Add to dashboard Cite

In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 μM), inhibition by α6 selective antagonist, furosemide (100 μM), and enhancement by THDOC (10–20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25–105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.

show abstract

Section: Discussionsupporting

confidence: 72%

Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype

Mohr

Kolotushkina

Kaplan

et al. 2013

Front. Neural Circuits

View full text Add to dashboard Cite

show abstract

“…Extrasynaptic GABA levels are also reduced, thereby decreasing CGN-I tonic . (C) Acute EtOH inhibits the Na + /K + -ATPase found on GoCs (and possibly also a quinidine-sensitive K + -channel [20]). Inhibition of these membrane proteins depolarizes the membrane potential of GoCs, thereby increasing spontaneous GoC firing and phasic GABA release onto CGNs.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, acute EtOH exposure increases both the frequency of sIPSCs driven by GoC firing and the magnitude of CGN-I tonic , and these effects are blocked by TTX [18]. Recordings from GoCs revealed that EtOH dose-dependently increases spontaneous GoC firing, an effect that appears to be, at least in part, a consequence of slight inhibition of the Na + /K + -ATPase [18], [19], [20]. In vivo electrophysiological studies indicate that acute EtOH exposure both increases spontaneous GoC firing and inhibits sensory responses of CGNs [21], [22].…”

Section: Introductionmentioning

confidence: 95%

Na+/K+-ATPase Inhibition Partially Mimics the Ethanol-Induced Increase of the Golgi Cell-Dependent Component of the Tonic GABAergic Current in Rat Cerebellar Granule Cells

et al. 2013

Self Cite

View full text Add to dashboard Cite

Cerebellar granule cells (CGNs) are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi cells (GoCs) mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-Itonic) is controversial. Earlier studies suggested that GoCs mediate a component of CGN-Itonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-Itonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-Itonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na+/K+-ATPase. We used whole-cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23–30). Under these conditions, we reliably detected a GoC-dependent component of CGN-Itonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-Itonic. Inhibition of the Na+/K+-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na+/K+-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.

show abstract

“…Tonic inhibition is mediated by extrasynaptic GABA A Rs that are activated by ambient levels of GABA whose source remains controversial (Brickley and Mody, 2012; Diaz et al, 2011; Lee et al, 2010). While GABAergic transmission at CGNs has been shown to be an important target for acute EtOH in the mature cerebellar cortex (Botta et al, 2010; Botta et al, 2007; Botta et al, 2011; Carta et al, 2004; Hanchar et al, 2005), the impact of EtOH exposure during development has not been explored. Importantly, the development of GABAergic transmission in other brain regions has been shown to be impaired in various models of 3 rd trimester-equivalent EtOH exposure (Everett et al, 2012; Hsiao et al, 1998; Zucca and Valenzuela, 2010).…”

Section: Introductionmentioning

confidence: 99%

Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABAA receptor δ subunit in cerebellar granule neurons and delays motor development in rats

et al. 2014

Self Cite

View full text Add to dashboard Cite

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 hours of exposure. EtOH levels gradually decreased to baseline 8 hrs 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 the expression of 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 GABAA 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.

show abstract

Excitation of Rat Cerebellar Golgi Cells by Ethanol: Further Characterization of the Mechanism

Cited by 18 publications

References 62 publications

Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype

Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype

Na+/K+-ATPase Inhibition Partially Mimics the Ethanol-Induced Increase of the Golgi Cell-Dependent Component of the Tonic GABAergic Current in Rat Cerebellar Granule Cells

Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABAA receptor δ subunit in cerebellar granule neurons and delays motor development in rats

Contact Info

Product

Resources

About