Dopamine suppresses persistent network activity via D1-like dopamine receptors in rat medial entorhinal cortex.

1.6 MB·English

by  Mayne, Elizabeth W

European Journal of Neuroscience
EuropeanJournal of Neuroscience,Vol. 37,pp. 1242–1247,2013 doi:10.1111/ejn.12125
MOLECULAR AND SYNAPTIC MECHANISMS
Dopamine suppresses persistent network activity via
D -like dopamine receptors in rat medial entorhinal
1
cortex
Elizabeth W. Mayne,1,2 Michael T. Craig,1,3,* Chris J. McBain2 and Ole Paulsen1,3
1Departmentof Physiology, AnatomyandGenetics,University ofOxford, Oxford,UK
2Program in DevelopmentalNeurobiology, Eunice KennedyShriver NationalInstituteof Child Healthand HumanDevelopment,
NationalInstitutesofHealth, Bethesda, MD,USA
3Departmentof Physiology, Development andNeuroscience, Physiological Laboratory,University of Cambridge, Cambridge, UK
Keywords: cortex,slow oscillation,UP states
Abstract
Corticalnetworksdisplaypersistentactivityintheformofperiodsofsustainedsynchronousdepolarizations(‘UPstates’)punctuated
byperiodsofrelativehyperpolarization(‘DOWNstates’),whichtogetherformtheslowoscillation.UPstatesareknowntobesynaptic-
allygeneratedandaresustainedbyadynamicbalanceofexcitationandinhibition,withfastionotropicglutamatergicexcitatoryand
GABAergicinhibitoryconductancesincreasingduringtheUPstate.Previously,workfromourgroupdemonstratedthatslowmetabo-
tropicGABAreceptorsalsoplayanimportantroleinterminatingtheUPstate,buttheeffectsofotherneuromodulatorsonthisnetwork
phenomenonhavereceivedlittleattention.Giventhatpersistentactivityisaneuralcorrelateofworkingmemoryandthatsignalling
throughdopaminereceptorshasbeenshowntobecriticalforworkingmemorytasks,weexaminedwhetherdopaminergicneurotrans-
missionaffectedtheslowoscillation.Here,usinganinvitromodeloftheslowoscillationinratmedialentorhinalcortex,weshowed
thatdopaminestronglyandreversiblysuppressedcorticalUPstates.WeshowedthatthiseffectwasmediatedthroughD -likeand
1
notD -likedopaminereceptors,andwefoundnoevidencethattonicdopaminergictransmissionaffectedUPstatesinourmodel.
2
Introduction
Neuronal networks display persistent activity, an important form of scale to balance excitatory conductances, both in vitro (Shu et al.,
circuit dynamics thought to underlie phenomena such as working 2003)andinvivo(Haideret al.,2006).
memory(reviewedbyMajor&Tank,2004).Oneexampleofpersis- Most studies of the circuit dynamics involved in generating UDS
tent activity is seenduring the slow oscillation, where neuronsoscil- have focussed on fast, ionotropic neurotransmission and less on the
late between periods of sustained depolarization and firing (‘UP roleplayedbyslowermetabotropicreceptors.Wepreviouslyreported
states’)punctuatedbyepochsofhyperpolarizationandreducedfiring that fast GABA receptor-mediated inhibition balances the UP state,
A
(‘DOWNstates’).Theslowoscillationcanbeobservedinvivoinan- whereas slow GABA receptor-mediated inhibition is important for
B
aesthetized (Steriade et al., 1993) or naturally sleeping (Contreras theterminationoftheUPstate(Mannet al.,2009),butwhetherother
et al., 1996) states as well as during quiet wakefulness (Petersen, neuromodulatorsaffecttheslowoscillationhasyettobedetermined.
2003). UP and DOWN states (UDS) can also be observed using Workingmemoryanditsneuralcorrelateintheprefrontalcortex,per-
reducedinvitropreparationssuchasslicescontainingthevisualcor- sistentactivity,areknowntobedependentupondopamine(Brozoski
tex (Sanchez-Vives & McCormick, 2000) or entorhinal cortex et al.,1979).Intheprefrontalcortex,dopaminecanreduceextracellu-
(Cunningham et al., 2006; Mann et al., 2009). Insights from these larGABAconcentrations(Grobin&Deutch,1998)viaamechanism
invitrostudiesshowthatUPstatesareassociatedwithanincreasein involving both D -like and D -like dopamine receptors (Bouthenet
1 2
bothexcitatoryandthatinhibitoryneurotransmission(Sanchez-Vives et al., 1987; Gao et al., 2001). Much like the prefrontal cortex, the
&McCormick,2000),andthat inhibitoryconductancesdynamically medialentorhinalcortex(mEC)receivesmultimodalinputfrommany
brainregions.ThemECformsoneofthemaininputandoutputsys-
temstothehippocampus(Cantoet al.,2008),sopersistentactivityin
the mEC may be involved in cognitive processes such as working
Correspondence:OlePaulsen,asabove. memory and spatial navigation. Diffuse neuromodulatory systems,
E-mail:[email protected] suchasdopaminergicprojections,mightthereforealsobeexpectedto
*Present address: Program in Developmental Neurobiology, Eunice Kennedy Shriver modulatethepersistentactivityofUDSinthemEC.
National Institute of Child Health and Human Development, National Institutes of Using a model of UDS in submerged mEC slices (Mann et al.,
Health,Bethesda,MD, 20892,USA 2009), we sought to determine whether the dopaminergic system
Received25September2012,revised27November2012,accepted11December2012 affected the slow oscillation. We found that dopamine rapidly and
Published2013.ThisarticleisaU.S.GovernmentworkandisinthepublicdomainintheUSA
Dopamine suppresses persistent networkactivity 1243
reversibly suppressed the incidence of UP states in rat mEC, and Results
that this effect was mediated through D -like dopamine receptors.
1 UP statesoccurspontaneously inthe medial entorhinal cortex
We found no evidence for the involvement of D -like receptors in
2 and aresuppressedbybathapplication of dopamine
the dopamine-mediated suppression of persistentactivity.
Whole-cell current-clamp recordings made from principal cells in
layer 3 of the mEC were used to monitor UDS. UP states occurred
Materials and methods spontaneously with an incidence of 2.9 (cid:3) 0.3/min and a mean dura-
tion of 5.2 (cid:3) 0.4 s (n = 37 slices, Fig. 1A and C). The mean spik-
Animals
ing frequency of principal cells during UP states was 0.6 (cid:3) 0.2 Hz.
AllexperimentswereconductedinaccordancewiththeUKAnimals The incidence of UP states was stable for at least 40 min after
Scientific Procedures Act (1986) and were subject to local ethical whole-cell configuration was achieved (Fig. 1B). Bath application of
review by the University of Oxford and the University of Cam- 10 lM dopamine reduced the incidence of UP states (Fig. 2A and
bridge. Wistarrats (Harlan, UK) were usedin allexperiments. B); after 10 min, spontaneous UP states were almost entirely sup-
pressed (UP state incidence, baseline vs. 10 lM dopamine:
3.3 (cid:3) 0.67/min vs. 0.04 (cid:3) 0.03/min; t = 4.8, P = 0.0089; n = 5;
Slice preparationand electrophysiology 4
paired t-test; Fig. 2C). Bath application of dopamine caused a small
Horizontal slices (400 lm) containing the mEC were prepared from but significant hyperpolarization of the resting membrane potential
postnatal day 14–21 rats of both sexes after decapitation under deep (baseline vs. 10 lM dopamine: (cid:1)62.1 (cid:3) 0.16 vs.
isoflurane-induced anaesthesia. Slices were cut in ice-cold (< 4 °C) (cid:1)64.3 (cid:3) 0.19 mV; t = 2.9, P= 0.044; n = 5; two-tailed paired t-
4
standard artificial cerebrospinal fluid containing (in mM): 126 NaCl, test). We next asked which type of dopamine receptor, D1-like or
3–3.5 KCl, 1.25 NaH PO , 2 MgSO , 2 CaCl and 26 NaHCO , D -like, mediates the effects of dopamine onUDS.
2 4 4 2 3 2
and were incubated at room temperature (22 (cid:1) 26 (cid:1)C) for 1 h in
interface conditions with standard artificial cerebrospinal fluid,
Dopaminergic suppressionofUP states ismediatedbyD -like
before being transferred to modified artificial cerebrospinal fluid 1
dopamine receptors
with reduced MgSO4 (1 mM) and CaCl2 (1.2 mM). Slices were
maintained in interface conditions prior to recording; they were then Toinvestigatethedopaminereceptorsubtypeinvolvedinsuppressing
mounted on a coverslip (coated with 0.1% poly-L-lysine in ultrapure persistent activity, we repeated the previous experiment in the pres-
H O) and transferred to a submerged-style recording chamber where ence of either the D -like receptor antagonist SCH23390 or the D -
2 1 2
they were superfused with modified artificial cerebrospinal fluid at 4 like receptor antagonist raclopride. Bath application of 10 lM
–5 mL/min at 32–34 °C. The maintenance of slices in interface con- SCH23390 prior to bath application of dopamine prevented the sup-
ditions was critical for the development of spontaneous UDS, and pressionofUPstates(Fig. 3A),withnosignificanteffectoneitherthe
the use of poly-L-lysine coverslips allowed slices to be mechanically duration (baseline vs. +10 lM SCH23390 vs. +10 lM dopamine:
stable under high perfusion rates and also improved laminar flow 5.5 (cid:3) 0.94 vs. 6.4 (cid:3) 1.10 vs. 3.9 (cid:3) 0.33 s; F = 4.9, P= 0.077;
2,5
across the slice; these conditions are known to promote spontaneous n = 6; repeated-measures ANOVA; Fig. 3B) or incidence (baseline vs.
network activityin submergedslices (Hajoset al., 2009). +10 lM SCH23390 vs. +10 lM dopamine: 4.8 (cid:3) 0.58/min vs.
Whole-cell current-clamp recordings were made from principal 5.3 (cid:3) 0.40/min vs. 3.9 (cid:3) 0.61/min; F = 2.3, P = 0.19; n = 6;
2,5
cells in layer 3 of the mEC, using glass pipettes pulled from stan- repeated-measures ANOVA; Fig. 3C) of UP states. Conversely, bath
dard borosilicate glass (6–8 MΩ) containing (in mM): 110 K gluco- applicationof200 nMraclopridefailedtopreventthesubsequentsup-
nate, 40 HEPES, 2 ATP-Mg, 0.3 GTP, 4 NaCl and 2–4 mg/mL pression of UP states after the application of dopamine (Fig. 3A),
biocytin (pH 7.2–7.3, osmolarity 275–290 mosmol/L). Membrane which significantly reduced UP state duration (baseline vs. +200 nM
potential values werenot correctedfor the liquid junctionpotential. raclopride vs. +10 lM dopamine: 5.1 (cid:3) 1.17 vs. 3.7 (cid:3) 0.68 vs.
0.4 (cid:3) 0.44 s; F = 15.5, P= 0.0091; n = 6; multiple comparisons
2,5
after repeated-measures ANOVA; Fig. 3D) and incidence (baseline vs.
Dataacquisition and analysis
+200 nM raclopride vs. +10 lM dopamine: 2.7 (cid:3) 0.73/min vs.
DatawererecordedusinganAxonMulticlamp700Bamplifier(Molec- 3.2 (cid:3) 0.74/min vs. 0.05 (cid:3) 0.05/min; F = 16.6, P= 0.0082;
2,5
ular Devices)andlow-passfilteredat2 kHz.Thesignalwas digitized n = 6;multiplecomparisonsafterrepeated-measuresANOVA;Fig. 3E).
at5 kHzusinganInstrutechITC-18onaPCrunningIgorPro(Wave- WeobservednosignificantrelationshipbetweenthebaselineUPstate
metrics Inc., Lake Oswego, OR, USA) using procedures written in- incidenceandthechangeinUPstateincidenceafterbathapplication
house. UDS transitions were monitored automatically using an algo- ofdopaminealone(r = (cid:1)0.50,P= 0.39;n = 5;Pearson’scorrelation
rithmthatdetectedchangesinDCmembranepotentialandmembrane test), dopamine and raclopride (r = 0.62, P = 0.18; n = 6) or dopa-
potential fluctuations using a moving average window method(Craig, mine and SCH23390 (r = 0.06, P = 0.92, n = 6; Pearson’s correla-
2011).AlldetectedUPstateswereconfirmedbyvisualinspection.Sta- tion test). We conclude that dopamine-induced suppression of
tisticalcomparisonsweremadeusingANOVAwithposthocBonferroni persistentactivityismediatedthroughD1-likereceptors.
multiple-comparison correction, or Student’s two-sample and pairedt-
tests as appropriate. Unless otherwise stated, all values are given as
Application ofaD -like receptor antagonistcanreverse
mean (cid:3) SEM. All data and statistical analyses were carried outusing 1
dopamine-induced suppressionofpersistent activity
eitherIgorProorGraphPadPrism(GraphPad,SanDiego,CA,USA).
Given that the D -like receptor antagonist SCH23390 could prevent
1
dopamine from suppressing UP states, we next sought to determine
Drugs andchemicals
whether this suppression was reversible. After recording spontane-
Raclopride and SCH23390 were purchased from Tocris Bioscience. ous UDS for 10 min, 10 lM dopamine was bath-applied. Subse-
All other chemicals were purchasedfrom Sigma-Aldrich. quently, we then applied either 10 lM SCH23390 or 200 nM
Published2013.ThisarticleisaU.S.GovernmentworkandisinthepublicdomainintheUSA
EuropeanJournalofNeuroscience,37,1242–1247
1244 E. W.Mayne et al.
A
10 mV
50 s 1 s
B C
10 4 U 15 8 U
P P
UP state duration (s) 2468 123 state incidence (per m UP state duration (s) 105 246 state incidence (per m
0 0 in) 0 0 in)
0 10 20 30 40
Time (min)
Fig.1. UPstatesinthemECarestableovertime.(A)Whole-cellcurrent-clamprecordingfromalayer3principalcellshowingthatUDSarestableoverlong
periods.Areamarkedbygreybarisshownontherightonanexpandedtimescale.(B)Theduration(greysquares)andincidence(blackcircles)ofUPstates
didnotchangeovertime(n=6).(C)DistributionofmeanUPstateduration(left)andincidence(right).ThemeanUPstatedurationwas5.2(cid:3)0.4sandthe
meanUPstateincidencewas2.9(cid:3)0.3/min(n=37slices).Whiskersontheboxplotsrepresentthemaximumandminimumvalues.
A +10 µM dopamine
20 mV
60 s
B C **
2.0 5
+10 µM dopamine n)
statemin) 1.5 per mi 4
Normalised UP incidence (per 10..05 state incidence ( 123
P
0.0 U 0
–4 0 4 8 Baseline +10 µM dopamine
Time (min)
Fig.2. Dopaminesuppressesthe incidenceofUPstates.(A)ExamplerecordingshowingthereductionintheincidenceofUPstatesafterbathapplicationof
10lM dopamine. (B) Time course of the depression of UP states over 10min after start of wash-in (n=14). (C) After 10min, dopamine had significantly
reducedthefrequencyofUPstates(n=5).**P<0.01,pairedt-test.
raclopride. Application of SCH23390 significantly reversed the sup- state incidence was not statistically significant (t = 1.5, P = 0.18;
5
pression of UP states, whereas raclopride had no effect (normalized one-sample t-test; h = normalized UP state incidence after
0
incidence of UP states at 25 min after washing antagonist, 10 lM SCH22390application was1).
SCG23390 vs. 200 nM raclopride: 1.4 (cid:3) 0.26/min vs. 0.30 (cid:3) 0.14/ In the previous experiment, application of 200 nM raclopride
min; t = 3.7, P= 0.004; n = 6; two-tailed Student’s t-test; appeared to cause a small but significant increase in UP state inci-
10
Fig. 4A). As well as reversing the dopamine-induced suppression of dence (Fig. 3E). To determine whether there was any tonic dopami-
UP states, it appeared that 10 lM SCH23390 might have increased nergic activity affecting the UP states, we bath-applied either 10 lM
the incidence above baseline values. However, this increase in UP SCH23390 or 200 nM raclopride for 40 min to observe the effect on
Published2013.ThisarticleisaU.S.GovernmentworkandisinthepublicdomainintheUSA
EuropeanJournalofNeuroscience,37,1242–1247
Dopamine suppresses persistent networkactivity 1245
A + 10 µM SCH23390 or 200 nM raclopride
n)
er mi 2.0 RSCacHlo2p3r3id9e0 ++ ddooppaammiinnee +10 µM dopamine
p
e (
c 1.5
n
e
d
ci
n
e i 1.0
at
st
P
U 0.5
d
e
s
mali 0.0
or 0 10 20 30 40
N
Time (min)
15 B n) 8 C
mi
n (s) per 6
duratio 10 ence ( 4
ate 5 ncid
UP st state i 2
0 P 0
e 0 e U e 0 e
n 9 n n 9 n
Baseli+10 µM SCH233 +10 µM dopami Baseli+10 µM SCH233+10 µM dopami
** * *
15 D n) 6 E
mi *
n (s) per
atio 10 ce ( 4
ate dur 5 nciden 2
st e i
P at
U st
0 P 0
e e e U e e e
n d n n d n
Baseli nM raclopri µM dopami Baseli nM raclopri µM dopami
0 0 0 0
0 1 0 1
2 + 2 +
+ +
Fig.3. Dopamine-inducedsuppressionofpersistentactivityismediatedviaD-likereceptors.(A)TheD-likereceptorantagonistSCH23390preventeddopa-
1 1
mine-induced suppressionof UPstates,whereastheD -likereceptorantagonistraclopridedidnot.(B)InthepresenceofSCH23390,nosignificantdifference
2
was observed in UP state duration upon application of dopamine. (C) In the presence of SCH23390, no significant difference was observed in UP state inci-
denceuponapplicationofdopamine.(D)Inthepresenceofraclopride,dopaminesignificantlyreducedthedurationofUPstates.(E)Inthepresenceof200nM
raclopride,dopaminealsosignificantlyreducedtheincidenceofUPstates(n=6).*P<0.05,**P<0.01;repeated-measuresANOVA.
UDS properties. Raclopride had no significant effect on UP state incidence (baseline vs. 10 lM SCH23390: 2.9 (cid:3) 0.62/min vs.
duration (baseline vs. 200 nM raclopride: 5.8 (cid:3) 1.8 vs. 4.3 (cid:3) 1.2 s; 3.6 (cid:3) 0.49/min; t5 = 1.9, P = 0.12; n = 6; two-tailed paired t-test;
t5 = 1.6, P = 0.17; n = 6; two-tailed paired t-test; Fig. 4B), inci- Fig. 4C) or spiking frequency (baseline vs. 10 lM SCH23390:
dence (baseline vs. 200 nM raclopride: 6.5 (cid:3) 3.5/min vs. 4.4 (cid:3) 2.1/ 0.52 (cid:3) 0.15 vs. 1.3 (cid:3) 0.32 Hz; t5 = 2.3, P= 0.070; n = 6; two-
min; t = 1.4, P= 0.23; n = 6; two-tailed paired t-test; Fig. 4B) or tailed paired t-test; Fig. 4C).
5
spiking frequency (baseline vs. 200 nM raclopride: 0.25 (cid:3) 0.07 vs. These data suggest that there was no detectable tonic effect of
0.97 (cid:3) 0.37 Hz; t = 1.9, P = 0.12; n = 6; two-tailed paired t-test; dopamine in our preparation, and we conclude that phasic applica-
5
Fig. 4B). Similarly, SCH23390 had no significant effect on UP state tion of dopamine can powerfully but reversibly block persistent
duration (baseline vs. 10 lM SCH23390: 5.7 (cid:3) 1.1 vs. 7.9 (cid:3) 1.9 s; activity in the mEC through a mechanism mediated by D1-like
t = 2.1, P = 0.092; n = 6; two-tailed paired t-test; Fig. 4C), dopamine receptors.
5
Published2013.ThisarticleisaU.S.GovernmentworkandisinthepublicdomainintheUSA
EuropeanJournalofNeuroscience,37,1242–1247
1246 E. W.Mayne et al.
+10 µM dopamine
A +10 µM SCH23390 or +200 nM raclopride
2.0
n) Dopamine + SCH23390
mi Dopamine + Raclopride
er
p
e ( 1.5
c
n
e
d
ci
n
e i 1.0
at
st
P
U
d 0.5
e
s
ali
m
or
N 0.0
0 10 20 30 40
Time (min)
15 B 15 C
Baseline Baseline
+200 nM raclopride +10 µM SCH23390
10 10
5 5
0 0
UP state duration (Ss)pike frequenPc ys t(atHez )incidence (per min) UP state duration (Ss)pike frequenPc ys t(aHtze) incidence (per min)
U U
Fig.4. A D-like antagonist can reverse dopamine-induced suppression of persistent activity. (A) Application of SCH23390 could reverse dopamine-induced
1
suppressionofUPstates,butapplicationofraclopridecouldnot(n=6).(BandC)SCH233390andraclopridealonehadnosignificanteffectonUPstatedura-
tion,incidenceorfiringfrequency(n=6).Repeated-measuresANOVA.
UP states by application of dopaminergic antagonists alone, suggest-
Discussion
ing that the off-target activation of 5HT and 5HT receptors had
1C 2C
The slow oscillation is a synaptically-driven oscillation, where UP aminimal effect inour model.
statesaregeneratedbyrecurrentactivitymediatedviaadynamicbal- Althoughithasbeenshownthat,inthestriatalspinyneurons,acti-
ance of excitatory and inhibitory conductances (Sanchez-Vives & vation of D receptors can truncate UP states (Plotkin et al., 2011),
2
McCormick,2000;Shuet al.,2003;Cunninghamet al.,2006;Haid- wefoundthattheeffectsofdopamineonmECUPstatesweremedi-
er et al., 2006). Whereas the contributions of fast, ionotropic excit- ated via D -like receptors. As dopamine is necessary for working
1
atory (Sanchez-Vives & McCormick, 2000; Compte et al., 2003; memory in the prefrontal cortex and can lower extracellular GABA
Shu et al., 2003) and inhibitory (Hasenstaub et al., 2005; Haider concentrations (Brozoski et al., 1979; Grobin & Deutch, 1998), one
et al., 2006) conductances to generating neocortical UP states are might have expected dopamine to increase excitation and thus
wellunderstood,theeffectsthatneuromodulatorshaveinmodulating enhancepersistentactivity,yet wesawtheoppositeresult. However,
persistent activity are less so. Previously, work from our group evenwithintheprefrontalcortex,theeffectsofdopaminecanappear
showedthat slowGABA receptors areinvolved in boththe sponta- contradictory and dependent upon experimental conditions (Seamans
B
neous and evoked termination of UP states (Mann et al., 2009), and & Yang, 2004). We chose a concentration of dopamine (10 lM) that
herewehaveshownthatdopaminecanstronglysuppressUPstates. was at the lower end of those reported in the literature, but that
We found that blockade of D -like receptors with the antagonist should still have activated both D -like and D -like receptors. There
1 1 2
SCH23390 prevented the dopamine-induced suppression of UP are a number of potential mechanisms that could explain why dopa-
states, although there still appeared tobeasmall, but non-significant mine suppresses persistent activity. First, an early study in the en-
reduction in UP state incidence (Fig. 3A). SCH23390 is also an torhinal cortex found that dopamine could inhibit layer 5 pyramidal
agonist at 5-HT and 5-HT receptors so it is possible that activa- cells by acting via D -like receptors to increase I (Rosenkranz &
1C 2C 1 H
tion of these receptors may have had an effect on network oscilla- Johnston, 2006), and a similar effect could potentially act on layer 3
tions. However, we saw no evidence for significant modulation of principal cells in our study. D -like receptors also depolarize
1
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EuropeanJournalofNeuroscience,37,1242–1247
Dopamine suppresses persistent networkactivity 1247
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EuropeanJournalofNeuroscience,37,1242–1247