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Department of Neurobiology and Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama
Submitted 6 September 2004; accepted in final form 28 September 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). Dopamine is an endogenous neuromodulator in the cerebral cortex and is believed to be important for normal brain processes (Bjorklund and Lindvall 1986; Williams and Goldman-Rakic 1995). There is strong evidence that alterations in dopamine function may play a role in pathogenesis of a number of neuropsychiatric diseases including epilepsy (Starr 1996) and schizophrenia (see Andreason 1996; Egan and Weinberger 1997; Grace et al. 1997; and Jaskiw and Weinberger 1992 for recent reviews). Our understanding of dopamine's action in the brain at the cellular and network level is still emerging. In vivo studies have shown that dopamine can both increase and decrease spontaneous firing of neocortical neurons (Bassant et al. 1990; Bradshaw et al. 1985; Bunney and Aghajanian 1976; Ferron et al. 1984; Pirot et al. 1992; Reader et al. 1979; Sesack and Bunney 1989; Thierry et al. 1992; Yang and Mogenson 1990). Dopamine may also favor long-lasting transitions of PFC neurons to a more excitable up state (Lewis and O'Donnell 2000). During short-term working memory processing, dopamine-dependent increases in firing of groups of PFC neurons have been observed (Fuster 1995; Goldman-Rakic 1995). In vitro electrophysiological experiments suggest that dopamine has multiple effects on PFC neurons. Both increases (Ceci et al. 1999; Gonzalez-Burgos et al. 2002; Gorelova and Yang 2000; Henze et al. 2000; Penit-Soria et al. 1987; Tseng and O'Donnell 2004; Wang and O'Donnell 2001; Yang and Seamans 1996) and decreases (Geijo-Barrientos and Pastore 1995) in postsynaptic excitability of pyramidal neurons have been reported following D1 receptor activation. In addition, changes in excitability mediated by D2 receptors have been reported (Gulledge and Jaffe 1998; 2001; Tseng and O'Donnell 2004). The effects of dopamine on synaptic responses are also complex and may be layer- and species-specific. AMPA receptor mediated excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells are depressed by a D1 receptor–mediated effect of dopamine (Law-Tho et al. 1994; Seamans et al. 2001), whereas N-methyl-D-aspartate (NMDA) responses have been reported to be both enhanced (Seamans et al. 2001) and depressed (Law-Tho et al. 1994). EPSCs in layers II/III are enhanced by dopamine in rats (Gonzalez-Islas and Hablitz 2003) but decreased in primates (Urban et al. 2002). Given this complexity and micro-heterogeneity, the net effect of dopamine modulation of local circuits in PFC is not easily predicted.
The cerebral cortex contains interconnected local and distant networks of excitatory and inhibitory neurons. Stability of activity in such networks depends on the balance between recurrent excitation and inhibition (Durstewitz et al. 2000a; Shu et al. 2003). A shift of the balance toward excitation may lead to the generation of epileptiform activity. The presence of massive recurrent excitatory connections that depend on inhibition for regulation has been implicated in the susceptibility of the neocortex and the hippocampus to develop epileptiform activity and seizures (McCormick and Conteras 2001). Modulatory influences strongly influence activity in thalamocortical (McCormick 1992; McCormick and Pape 1990) and neocortical circuits (McCormick et al. 1993).
Dopamine is known to modulate epileptiform discharges both in vivo (Alam and Starr 1992, 1993b, 1994a; George and Kulkarni 1997) and in vitro (Alam and Starr 1993b, 1994b; Cepeda et al. 1999; Siniscalchi et al. 1997; Suppes et al. 1985). In vivo studies in different models of epilepsy have suggested that dopamine may have a pro-convulsant effect mediated by D1 receptors and an anti-convulsant effect via D2 receptors (see Starr 1996 for review). A dopamine-mediated recruitment of neurons in local excitatory circuits and synchronization of activity in these neurons may underlie these effects of dopamine in neocortex. Local excitatory neocortical networks are complexes of interconnected pyramidal neurons. Since dopamine has diverse effects on these neurons, the action of dopamine in such networks is difficult to predict based on recordings from individual pyramidal neurons or unitary excitatory connections. The aim of this work was to investigate dopamine's ability to modulate activity in the local excitatory circuits in PFC. Using a combination of whole cell recording and voltage-sensitive dye imaging, we have shown that dopamine, via D1 receptors, enhances local spatiotemporal spread of synaptic activity and lowers the threshold for evoking epileptiform discharges in neocortex. A preliminary account of some of these findings has been published (Hablitz and Gonzalez-Islas 2002).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Neocortical slices were prepared from Sprague-Dawley rats (25–30 days old). Animals were handled and housed according to the National Institutes of Health Committee on Laboratory Animal Resources guidelines. All experimental protocols were approved by the UAB Institutional Animal Care and Use Committee. Every effort was made to minimize pain and discomfort. Rats were anesthetized with ketamine and decapitated. The brain was removed and quickly placed in ice-cold saline which contained (in mM) 125 NaCl, 3.5 KCl, 26 NaHCO3, 10 D-glucose, 3 MgCl2, and 1 CaCl2. Coronal slices (300 µm thick) were cut on a Vibratome (Ted Pella, Redding, CA) from a block of brain containing PFC. The anterior cingulate cortex and the shoulder or Fr2 region of the frontal cortex (Paxinos and Watson 1986) were used for recording. Slices were stored for 45 min at 37°C and kept at room temperature until recording. The storage solution contained (in mM) 125 NaCl, 3.5 KCl, 26 NaHCO3, 10 D-glucose, 2.5 CaCl2, and 1.3 MgCl2. The solution was bubbled with 95%O2-5%CO2 to maintain pH around 7.4. Individual slices were subsequently transferred to a recording chamber continuously perfused (3 ml/min) with oxygenated saline at 22–23°C. For electrophysiological studies, neurons were visualized using a Zeiss Axioskop FS microscope equipped with Nomarski optics, a 40x-water immersion lens, and infrared illumination. Layer II/III pyramidal neurons were identified by their pyramidal shape, presence of a prominent apical dendrite, distance from the pial surface, and their regular spiking properties. Some of the cells were labeled with biocytin for confirmation of their identity.
Whole cell recording
Whole cell voltage-clamp recordings were obtained as described previously (Gonzalez-Islas and Hablitz 2003). A holding potential of –70 mV was used throughout. Patch electrodes had resistances of around 3 M
. Series resistance during recording varied from 10 to 20 M and was not compensated. Recordings were terminated whenever significant increases (>20%) in series resistance occurred. The intracellular solution for recording synaptic currents contained (in mM) 125 K-gluconate, 10 KCl, 10 HEPES, 2 Mg-ATP, 0.2 Na-GTP, and 0.5 EGTA. pH and osmolarity were adjusted to 7.3 and 290 mOsm, respectively. Bicuculline methiodide (10 µM) was bath-applied to block GABAA receptor–mediated inhibitory postsynaptic currents (IPSCs). Synaptic responses were evoked with a bipolar stimulating electrode (twisted pair of 25-µm Formvar-insulated nichrome wires) positioned in layer IV-V, at a distance of 150–200 µm below the recording pipette. Stimuli were square wave current pulses 100–400 µA in amplitude and 50–100 µs in duration. A stimulation frequency of 0.05 Hz was used. Acquisition of experimental data consisted of 15–30 consecutive responses. Signals were recoded using a Warner PC 505A amplifier (Warner Instruments, Hamden, CT). Responses were filtered at 5 kHz, digitized at 10–20 kHz via a Digidata 1200B interface (Axon Instruments, Foster City, CA), and analyzed using Clampfit 8.0 software (Axon Instruments).
Voltage-sensitive dye imaging
Slices were incubated in saline containing the voltage-sensitive fluorescent dye N-(3-(triethylammonium)propyl)-4-(4-(p-diethylaminophenyl)butadienyl)pyridinium dibromide (RH 414) (Grinvald et al. 1988) (30 µM) for 45–90 min at room temperature. After incubation in the dye, the slice was transferred to a recording chamber continuously perfused (3 ml/min) with oxygenated saline at 22–23°C. Excess dye was washed out for 
30 min prior to recording. The same area of PFC used for whole cell recording was chosen for imaging. Similar bipolar electrodes were used for stimulation; the stimulation site and strength were also similar to those used in whole cell recordings. Frequency of stimulation was once every minute.
Activity-dependent changes in fluorescence were detected using a Neuroplex 464 diode array (Red Shirt Imaging, Fairfield, CT). A sampling rate of 1.6 KHz was employed allowing frames to be acquired at 0.6-ms intervals. To excite the dye, light from a 100-W halogen lamp was passed through a 535 ± 40-nm filter. A computer-controlled shutter was used to limit illumination and minimize toxic effects of the dye. The emitted light was focused on the diode array after passing through a 590-nm long-pass filter. The optical signals were amplified and stored on a computer. The resting light intensity measured for each detector was used to normalize all fluorescence measurements. Dye bleaching was corrected using measurements taken in the absence of stimulation. All optical signals are represented as percent changes in fluorescence (
F/F, where F is the fluorescence light intensity of the stained slice during illumination without evoked activity and F is the fluorescence change during neuronal activity). A decrease in fluorescence, associated with membrane depolarization, is plotted as an upward deflection in all figures. Data are displayed as pseudocolor images for visualizing spatiotemporal patterns of activity. Pseudocolor scaling was fixed for all frames in a given figure.
Drug application
Dopamine was used as the endogenous agonist for dopamine receptors. R(+)-6-chloro-7,8-dihydroxy-1-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) and R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) were used as a selective D1 agonist and antagonist, respectively. Quinpirole and S-(–)-eticlopride hydrochloride were used as a selective D2 agonist and antagonist, respectively. All the drugs were applied in bath. After recording control responses, dopamine and dopaminergic agents were bath applied for 4 min prior to acquisition of experimental data; bath application of the drug was then continued for the duration of acquisition of experimental data. For experiments with the dopamine antagonists, the antagonist was present in both the control and agonist-containing solutions. Drugs were stored in frozen stock solution and dissolved in the saline prior to each experiment. Sodium metabisulfite (50 µM) was used to protect against oxidation (Sutor and Ten Bruggencate 1990). Dopamine, SKF 81297, and eticlopride were purchased from Sigma (St. Louis, MO), whereas SCH 23390 and quinpirole were purchased from Tocris Cookson (Ellisville, MO).
Data analysis and statistics
For analyzing data from imaging experiments, a region of interest (ROI) that included visually obvious activity along with a surrounding area with no apparent activity was chosen in the control recording. Peak signal amplitudes (peak F/F, where F is the fluorescence light intensity at the diode without stimulation and F is the fluorescence change after stimulation) of five diodes outside the ROI were averaged to obtain the baseline noise level. Diodes in the ROI that showed peak signal amplitudes above twice that of the baseline noise were selected for analysis. These same diodes were selected for analysis in the image taken after drug application in that experiment. The peak signal amplitudes of these diodes were summed to get the "peak activity." Lateral spread of activity was estimated by calculating the distance between the two most extreme diodes in the ROI showing activity above twice the baseline noise. Duration of activity was calculated by estimating the time interval between the first and the last frames of an acquisition showing activity. These three parameters were estimated under control conditions and 10 min after drug application in all the imaging experiments.
Statistical comparisons were done using Student's t-test. P < 0.05 was considered significant. Statistical calculations were done with the help of OriginPro 7.0 software. Data are expressed as mean ± SD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Whole cell voltage-clamp recordings were obtained from layer II/III pyramidal neurons in the PFC. In the presence of bicuculline (10 µM) to block GABAA receptor–mediated inhibition, weak intracortical stimulation evoked small amplitude EPSCs. The stimulation level employed did not evoke epileptiform activity under control conditions. Figure 1A shows superimposed traces of 15 EPSCs under control conditions, at a holding potential of –70 mV. The initial EPSC was occasionally followed by multiple, smaller amplitude, presumably polysynaptic, EPSCs. Application of 1 µM SKF 81297 increased EPSC amplitude (Fig. 1B), as reported previously (Gonzalez-Islas and Hablitz 2003; Seamans et al. 2001). This was accompanied by the occurrence of late epileptiform discharges of variable latency and amplitude. The responses in Fig. 1, A and B, were averaged and are shown superimposed in Fig. 1C. Similar results were obtained in 7 of 10 cells tested with the D1 agonist SKF 81297 (1 µM) and 8 of 10 tested with 30–60 µM dopamine.
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Voltage-sensitive dye imaging
Epileptiform discharges are generally thought to represent the synchronous discharge of a local population of neurons (Ayala et al. 1970; Gutnick et al. 1982). An important factor for epileptogenesis is the degree to which a population of neurons becomes synchronized and whether this activity spreads or propagates through the brain. The factors that determine whether a discharge stays localized or spreads are poorly understood. We therefore used imaging techniques to determine if dopamine could influence the spatiotemporal pattern of activation in local neocortical circuits.
A hexagonal photodiode array with 464 diodes was used for imaging. Using a 10x objective, the hexagonal array imaged an area with a width and height of approximately 1.8 mm, covering from pia to white matter (Fig. 2A). With weak intracortical stimulation in the presence of 10 µM bicuculline, there was an initial activation of a small region in cortical layers above the stimulation site (Fig. 2C). Activity then spread to the adjacent cortex before returning to control levels. Following bath application of the D1 receptor agonist SKF 81297 (1 µM), response amplitudes were increased as seen by the appearance of increased number of red pixels (Fig. 2D). The increases were clearly evident in dye signals in representative diodes (Fig. 2B). The "peak activity" (the sum of signal peaks in diodes showing activity; see METHODS) significantly increased (Fig. 5) from 0.1561 ± 0.0631 in controls to 0.2114 ± 0.0920 after SKF 81297 (1 µM) application (n = 11, P = 0.0089). The spatiotemporal spread of activity also was enhanced (Fig. 5). Activity spread laterally to greater distances (589 ± 126 vs. 964 ± 170 µm; n = 11) and persisted for a longer period of time (55 ± 16 vs. 93 ± 35 ms; n = 11) after the application of the D1 receptor agonist (Fig. 5). Both the lateral spread (P = 0.0002) and duration (P = 0.0069) of activity were significantly increased over control. Similar results were obtained in 11 of 23 slices (from 12 animals) tested with SKF 81297 (1 µM). In four of six slices (from 4 animals), bath application of 60 µM dopamine also produced significant increases in lateral spread, duration, and peak amplitude of evoked activity (Fig. 5). There was a 122% increase in lateral spread of activity (431 ± 128 vs. 956 ± 215 µm; n = 4; P = 0.0021), whereas duration of activity increased by 185% (94 ± 40 vs. 174 ± 61 ms; n = 4; P = 0.0072) after dopamine application; "peak activity" increased from 0.1325 ± 0.0353 to 0.1854 ± 0.0411 (n = 4; P = 0.0003). Increases in activity appeared 6–9 min following bath application of dopamine or SKF 81297. The observed changes were reversible on washing. These findings suggest that the dopamine-induced increases in EPSC amplitudes are associated with enhanced spread of activity in local cortical networks.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). In addition, this enhancement was associated with an increase in recurrent EPSPs, which could result in the triggering of epileptiform activity. Using voltage-sensitive dye imaging, we have shown that dopamine enhancement of EPSCs resulted in alterations in the spatiotemporal pattern of activity in local cortical circuits. Dopamine could either enhance activity locally or, if enhancement was strong enough, result in epileptiform events which propagated throughout the slice. Dopamine effects were blocked by SCH 23390 indicating D1 receptor involvement. These results indicate that, in the disinhibited rat neocortex, D1 receptors have significant proconvulsant activity. Dopamine and epilepsy
In vivo studies have shown that dopamine can affect seizures in several different models of epilepsy (see Starr 1996 for review). The reported effects of dopamine receptor activation were variable across seizure models. Most of the early work was done with nonselective dopamine agonists and antagonists. The nonselective dopamine agonist apomorphine primarily had an anticonvulsant effect (Loscher and Czuczwar 1986; Ogren and Pakh 1993; Turski et al. 1988), whereas the nonselective dopamine antagonist haloperidol was proconvulsant in several seizure models (Sato et al. 1980; Turski et al. 1988; Warter et al. 1988). D1 selective agonists had a proconvulsant effect in the pilocarpine model of epilepsy (Al-Tajir et al. 1990; Barone et al. 1990; Burke et al. 1990; Starr and Starr 1993a, b; Turski et al. 1990). SKF 38393, a selective D1 agonist, increased the frequency, severity, and lethality of pilocarpine-induced seizures in rats, effects which were blocked by the selective D1 antagonist SCH 23390 (Al-Tajir et al. 1990; Barone et al. 1990; Turski et al. 1990). Intrahippocampal injection of SCH 23390 increased the threshold for pilocarpine-induced motor seizures and reduced their severity in rats, suggesting a role for hippocampal D1 receptors in lowering seizure threshold (Alam and Starr 1992). Our results are consistent with the findings of these in vivo studies and show that, in disinhibited neocortical slices, D1 receptor stimulation has a proconvulsant effect.
Initial in vitro studies showed that low concentrations (1 µM) of dopamine slowed down the rhythmic paroxysmal activity induced in CA1 neurons by low calcium/high magnesium solutions, whereas high concentrations (100 µM) of dopamine accelerated them (Haas et al. 1984). Other studies have shown that bath application of the D1 agonist SKF 38393 decreases low calcium-induced spontaneous epileptiform discharges in CA1 neurons, an effect blocked by pretreatment with the D1 antagonist SCH 23390 (Smialowski 1990). Penicillin-induced epileptiform discharges were also decreased in frequency by dopamine (Suppes et al. 1985). In the neocortex, the duration and frequency of spontaneously occurring epileptiform discharges induced by 4-aminopyridine in magnesium-free external solution were also reduced in a reversible manner by dopamine (Siniscalchi et al. 1997). The dopamine receptor subtype involved was not determined. Similarly, dopamine and the D1 agonist SKF 38393 suppressed zero magnesium-induced paroxysmal discharges in rat cingulate cortex slices (Alam and Starr 1993a). However, dopamine, at low concentrations, was also reported to have a facilitatory effect on the number of secondary depolarizing afterpotentials following initial paroxysmal spikes (Alam and Starr 1994b). The variety in dopamine receptors and their effecter mechanisms, coupled with regional heterogeneity in expression, complicates understanding of the dopamine system and may underlie the diversity of effects on epileptiform discharges. The facilitatory effects seen in this study are in agreement with studies on slices of cortical tissue from children undergoing epilepsy surgery where dopamine and the D1 agonist SKF 38393 enhanced NMDA excitatory postsynaptic potentials (EPSPs) and favored emergence of epileptic activity (Cepeda et al. 1999).
Dopamine-induced changes in spatiotemporal patterns of activity
Imaging of voltage-sensitive dye signals has emerged as a powerful technique for studying epileptiform activity in brain slices (Demir et al. 1998; Kita et al. 1999; Sutor et al. 1994). Using this technique, it has been shown that, under normal conditions, moderate intensity stimulation can generate "ensemble activity," a polysynaptic, all-or-none population activity in a local neocortical network (Wu et al. 2001). Spatially restricted epileptiform activity was also observed in neocortex following partial blockade of GABAA receptors (Langenstroth et al. 1996). Kita et al. (1999) found that epileptiform responses evoked by subcortical white matter stimulation in the presence of bicuculline were modulated by dopamine agonists. Both D1 and D2 receptor agonists reduced the peak optical response but did not alter the shape or size of the area of cortex responding to stimulation. There recordings were from the ventral rostral aspect of the frontal cortex, and averaged responses were analyzed. In this study, we observed spatially restricted activity in the presence of bicuculline when weak stimulation was used. The spatially restricted activity originated near the site of stimulation and spread rapidly in both vertical and horizontal directions. Increasing the stimulus intensity evoked epileptiform activity with spatiotemporal characteristics resembling those described previously using voltage-sensitive dye imaging (Albowitz et al. 1998; Demir et al. 1998; Sutor et al. 1994; Wu et al. 2001). Epileptiform activity involved all layers of cortex with the largest amplitude signals occurring in layers II/III, as described previously in rat (Sutor et al. 1994), guinea pig (Albowitz et al. 1990), and human (Albowitz et al. 1998) neocortex.
The spatially restricted enhanced activity seen after D1 receptor activation is likely to reflect recurrent activation via local excitatory axon collaterals. In this study, increased recurrent EPSCs were prominent following application of dopamine or the D1 receptor agonist SKF 81297. Subthreshold depolarization of a population of cells has been suggested to underlie formation of "dynamic ensembles" (Wu et al. 1999). Such assemblies have persistent activation, as also observed here. This long-lasting activity may enhance synchronization, activation of adjacent neurons and initiation of epileptiform activity.
Modulation and epileptogenesis
Prerequisites for the generation of synchronized epileptiform activity observed in vitro include 1) an intrinsic ability of the neurons to generate bursts, 2) powerful excitatory inputs through recurrent collateral connections to other cells in the local circuit sufficient to allow spread and divergence of the burst activity, and 3) an adequate decrease in inhibition in the network of neurons involved (Wong et al. 1984, 1986). The synchronization increases and sharpens, and its latency decreases as the level of disinhibition increases (Traub et al. 1987). These results indicate that an additional important variable in this process may be input from neuromodulatory system and that dopamine can have significant proconvulsant actions, in part by increasing recurrent excitation and enhancing synchronization.
The mechanisms underlying transition from spatiotemporally restricted interictal discharge to a widespread and more prolonged ictal discharge are not clear. Hippocampal modeling studies (Traub et al. 1993a, b, 1994) have suggested that intrinsic membrane properties (rhythmic dendritic bursts mediated by dendritic calcium spikes) along with activation of both AMPA and NMDA receptors may govern the spatiotemporal pattern of epileptic discharges. Any intervention that facilitates one or more of these factors involved in synchronization could facilitate generation and/or spread of epileptiform activity in the network. Previous studies have shown that D1 dopamine receptors potentiate NMDA-mediated excitability increases in neocortical neurons (Wang and O'Donnell 2001). Our results suggest that dopamine has an overall facilitatory effect on local excitatory connections in upper cortical layers. We have shown previously that AMPA and NMDA receptor–mediated EPSCs are both enhanced by D1 receptor activation (Gonzalez-Islas and Hablitz 2003). These results indicate that recurrent EPSCs are also enhanced. The net result of these alterations is a decrease in threshold for stimulus evoked epileptiform discharges and an enhanced susceptibility for increased spatiotemporal spread of epileptiform activity.
Dopamine and local circuit activity
PFC neurons are known to encode working memory by sustaining firing in the absence of afferent input. This persistent firing may arise from recurrent excitation within the local PFC networks (Goldman-Rakic 1995). Dopamine, via D1 receptor–mediated mechanisms, facilitates working memory function by increasing the signal-to-noise ratio, which minimizes the background noise thereby allowing the network to sustain specific task-related activity in the face of distracting inputs (Durstewitz and Seamans 2002; Durstewitz et al. 2000a, b). While extensive horizontal excitatory connections in layers II/III in the PFC may support such recurrent excitation within the local network (Gonzalez-Burgos et al. 2000; Kritzer and Goldman-Rakic 1995), a balance between excitation and inhibition appears to be crucial in initiating and maintaining stable periods of persistent activity (Fellous and Sejnowski 2003; Shu et al. 2003). In this study, when using weak excitation in disinhibited slices, dopamine increased synchronization in the local excitatory neocortex. When inhibition is intact, such localized increase in activity may stay spatially and temporally restricted by recurrent inhibition (Compte et al. 2000; Constantinidis et al. 2002). Thus dopamine-mediated synchronization of local excitatory networks in the PFC may play a role in physiologic functions like working memory. As the level of excitation increased in this study, the degree of synchronization increased, eventually producing epileptiform activity. Therefore the same dopamine-mediated synchronization can give rise to a pathologic phenomenon when the level of excitation is high and inhibition is low.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. J. Hablitz, Dept. of Neurobiology, Univ. of Alabama at Birmingham, Birmingham, AL 35294 (E-mail: hablitz{at}nrc.uab.edu)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Alam AM and Starr MS. Dopaminergic modulation of pilocarpine-induced motor seizures in the rat: the role of hippocampal dopamine D1 receptors. Eur J Pharmacol 222: 227–232, 1992.[CrossRef][ISI][Medline]
Alam AM and Starr MS. D1 agonists suppress zero Mg2+-induced epileptiform activity in the rat cingulate cortex slice. Neuroreport 5: 78–80, 1993a.[ISI][Medline]
Alam AM and Starr MS. Dopaminergic modulation of pilocarpine-induced motor seizures in the rat: the role of hippocampal D2 receptors. Neuroscience 53: 425–431, 1993b.[CrossRef][ISI][Medline]
Alam AM and Starr MS. Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat. Neuroscience 60: 1039–1047, 1994a.[CrossRef][ISI][Medline]
Alam AM and Starr MS. Bimodal effects of dopamine D2 receptor agonists on zero Mg2+-induced epileptiform activity in the rat cingulate cortex slice. Exp Brain Res 102: 75–83, 1994b.[ISI][Medline]
Albowitz B, Kuhnt U, and Ehrenreich L. Optical imaging of epileptiform voltage changes in the neocortical slice. Exp Brain Res 81: 241–256, 1990.[ISI][Medline]
Albowitz B, Kuhnt U, Kohling R, Lucke A, Straub H, Speckmann E-J, Tuxhorn I, Wolf P, Pannek H, and Oppel F. Spatio-temporal distribution of epileptiform activity in slices from human neocortex: recordings with voltage-sensitive dyes. Epilepsy Res 32: 224–232, 1998.[CrossRef][ISI][Medline]
Andreason NC. Pieces of the schizophrenia puzzle fall into place. Neuron 16: 697–700, 1996.[CrossRef][ISI][Medline]
Ayala GF, Matsumoto H, and Gumnit RJ. Excitability changes and inhibitory mechanisms in neocortical neurons during seizures. J Neurophysiol 33: 73–85, 1970.
Barone P, Parashos SA, Palma V, Marin C, Campanella G, and Chase TN. Dopamine D1 receptor modulation of pilocarpine-induced convulsions. Neuroscience 34: 209–217, 1990.[CrossRef][ISI][Medline]
Bassant MH, Ennouri K, and Lamour Y. Effects of iotophoretically applied monoamines on somatosensory cortical neurons of unanesthetized rats. Neuroscience 39: 431–439, 1990.[CrossRef][ISI][Medline]
Bjorklund A and Lindvall O. Dopamine-containing systems in the CNS. In: Handbook of Chemical Neuroanatomy:Classical Transmitter in the Rat, edited by Bjorklund A and Hokfelt T. Amsterdam: Elsevier, 1984, p. 55–122.
Bjorklund A and Lindvall O. Catecholaminergic regulatory systems. In: Handbook of Physiology. The Nervous System. Washington, DC: American Physiology Society, 1986, p. 155–235.
Bradshaw CM, Sheridan RD, and Szabadi E. Excitatory neuronal responses to dopamine in the cerebral cortex: involvement of D2 but not D1 dopamine receptors. Brit J Pharmacol 86: 483–490, 1985.[ISI][Medline]
Bunney BS and Aghajanian GK. Dopamine and norepinephrine innervated cells in the rat prefrontal cortex: pharmacological differentiation using microiontophoretic techniques. Life Sci 19: 1783–1792, 1976.[CrossRef][ISI][Medline]
Burke K, Chandler CJ, Starr BS, and Starr MS. Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse. Pharmacol Biochem Behav 36: 729–733, 1990.
Ceci A, Brambilla A, Duranti P, Grauert M, Grippa N, and Borsini F. Effect of antipsychotic drugs and selective dopaminergic antagonists on dopamine-induced facilitatory activity in prelimbic cortical pyramidal neurons. An in vitro study. Neuroscience 93: 107–115, 1999.[CrossRef][ISI][Medline]
Cepeda C, Li Z, Cromwell HC, Altemus KL, Crawford CA, Nansen EA, Ariano MA, Sibley DR, Peacock WJ, Mathern GW, and Levine MS. Electrophysiological and morphological analyses of cortical neurons obtained from children with catastrophic epilepsy: dopamine receptor modulation of glutamatergic responses. Dev Neurosci 21: 223–235, 1999.[CrossRef][ISI][Medline]
Compte A, Brunel N, Goldman-Rakic PS, and Wang XJ. Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model. Cereb Cortex 10: 910–923, 2000.
Constantinidis C, Williams GV, and Goldman-Rakic PS. A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nature Neurosci 5: 175–180, 2002.[CrossRef][ISI][Medline]
Demir R, Haberly LB, and Jackson MB. Voltage imaging of epileptiform activity in slices from rat piriform cortex:onset and propagation. J Neurophysiol 80: 2727–2742, 1998.
Durstewitz D and Seamans JK. The computational role of dopamine D1 receptors in working memory. Neural Networks 15: 561–572, 2002.[CrossRef][ISI][Medline]
Durstewitz D, Seamans JK, and Sejnowski TJ. Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 83: 1733–1750, 2000a.
Durstewitz D, Seamans JK, and Sejnowski TJ. Neurocomputational models of working memory. Nature Neurosci 3: 1184–1191, 2000b.
Egan MF and Weinberger D. Neurobiology of schizophrenia. Curr Opin Neurobiol 3: 701–707, 1997.
Fellous JM and Sejnowski TJ. Regulation of persistent activity by background inhibition in an in vitro model of a cortical microcircuit. Cereb Cortex 13: 1232–1241, 2003.
Ferron A, Thierry AM, LeDouarin C, and Glowinski J. Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex. Brain Res 302: 257–265, 1984.[CrossRef][ISI][Medline]
Fuster JM. Memory in the Cerebral Cortex: An Empirical Approach to Neural Networks in Human and Non-Human Primate. Cambridge: MIT Press, 1995.
Geijo-Barrientos E and Pastore C. The effects of dopamine on the subthreshold electrophysiological responses of rat prefrontal cortex neurons in vitro. Eur J Neurosci 7: 358–366, 1995.[CrossRef][ISI][Medline]
George B and Kulkarni S. Dopaminergic modulation of lithium/pilocarpine-induced status epilepticus in rats. Methods Find Exp Clin Pharmacol 19: 481–488, 1997.[ISI][Medline]
Goldman-Rakic PS. Cellular basis of working memory. Neuron 14: 477–485, 1995.[CrossRef][ISI][Medline]
Gonzalez-Burgos G, Barrionuevo G, and Lewis DA. Horizontal synaptic connections in monkey prefrontal cortex: an in vitro electrophysiology study. Cereb Cortex 10: 82–92, 2000.
Gonzalez-Burgos G, Kroner S, Krimer LS, Seamans JK, Urban NN, Henze DA, Lewis DA, and Barrionuevo G. Dopamine modulation of neuronal function in the monkey prefrontal cortex. Physiol Behav 77: 537–543, 2002.[CrossRef][Medline]
Gonzalez-Islas C and Hablitz JJ. Dopamine enhances EPSCs in layer II-III pyramidal neurons in rat prefrontal cortex. J Neurosci 23: 867–875, 2003.
Gorelova N and Yang CR. Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro. J Neurophysiol 84: 75–87, 2000.
Grace AA, Bunney BS, Moore H, and Todd CL. Dopamine-cell depolarization as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 20: 31–37, 1997.[CrossRef][ISI][Medline]
Grinvald A, Frostig RD, Lieke EE, and Hildesheim R. Optical imaging of neuronal activity. Physiol Rev 68: 1285–1366, 1988.
Gulledge AT and Jaffe DB. Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex. J Neurosci 18: 9139–9151, 1998.
Gulledge AT and Jaffe DB. Multiple effects of dopamine on layer V pyramidal cell excitability in rat prefrontal cortex. J Neurophysiol 86: 586–595, 2001.
Gutnick MJ, Connors BW, and Prince DA. Mechanisms of neocortical epileptogenesis in vitro. J Neurophysiol 48: 1321–1335, 1982.
Haas HL, Jefferys JG, Slater NT, and Carpenter DO. Modulation of low calcium induced field bursts in the hippocampaus by monoamines and cholinomimetics. Pfluegers 400: 28–33, 1984.
Hablitz JJ and Gonzalez-Islas C. Dopamine alters threshold for initiation of epileptiform activity in rat neocortex. Epilepsia 43(7 suppl): 129, 2002.
Henze DA, Gonzalez-Burgos GR, Urban NN, Lewis DA, and Barrionuevo G. Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex. J Neurophysiol 84: 2799–2809, 2000.
Jaskiw GE and Weinberger D. Dopamine and schizophrenia—a cortically corrective perspective. Semin Neurosci 4: 179–188, 1992.
Kita H, Oda K, and Murase K. Effects of dopamine agonists and antagonists on optical responses evoked in rat frontal cortex slices after stimulation of the subcortical white matter. Exp Brain Res 125: 383–388, 1999.[CrossRef][ISI][Medline]
Kritzer MF and Goldman-Rakic PS. Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the Rhesus monkey. J Comp Neurol 359: 131–143, 1995.[CrossRef][ISI][Medline]
Langenstroth M, Albowitz B, and Kuhnt U. Partial suppression of GABAA-mediated inhibition induces spatially restricted epileptiform activity in guinea pig neocortical slices. Neurosci Lett 210: 103–106, 1996.[CrossRef][ISI][Medline]
Law-Tho D, Hirsch JC, and Crepel F. Dopamine modulation of synaptic transmission in rat prefrontal cortex: an in vitro electrophysiological study. Neurosci Res 21: 151–160, 1994.[CrossRef][ISI][Medline]
Lewis BL and O'Donnell P. Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential ‘up’ states in pyramidal neurons via D1 dopamine receptors. Cereb Cortex 10: 1168–1175, 2000.
Loscher W and Czuczwar SJ. Studies on the involvement of dopamine D-1 and D-2 receptors in the anticonvulsant effect of dopamine agonists in various rodent models of epilepsy. Eur J Pharmacol 128: 55–65, 1986.[CrossRef][ISI][Medline]
McCormick DA. Neurotransmitter actions in the thalamus and cerebral cortex and their role in the neuromodulation of thalamocortical activity. Prog Neurobiol 39: 337–388, 1992.[CrossRef][ISI][Medline]
McCormick DA and Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 63: 815–846, 2001.[CrossRef][ISI][Medline]
McCormick DA and Pape H-C. Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurones. J Physiol 431: 319–342, 1990.
McCormick DA, Wang Z, and Huguenard JR. Neurotransmitter control of neocortical neuronal activity and excitability. Cereb Cortex 3: 387–398, 1993.
Ogren SO and Pakh B. Effects of dopamine D1 and D2 receptor agonists and antagonists on seizures induced by chemoconvulsants in mice. Pharmacol Toxicol 72: 213–220, 1993.[ISI][Medline]
Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates. Sydney, Australia: Academic, 1986.
Penit-Soria J, Audinat E, and Crepel F. Excitation of rat prefrontal cortical neurons by dopamine: an in vitro electrophysiological study. Brain Res 425: 263–274, 1987.[CrossRef][ISI][Medline]
Pirot S, Godbout R, Mantz J, Tassin J-P, Glowinski J, and Thierry A-M. Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components. Neuroscience 49: 857–865, 1992.[CrossRef][ISI][Medline]
Reader TA, Ferron A, Descarries L, and Jasper HH. Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies. Brain Res 160: 217–229, 1979.[CrossRef][ISI][Medline]
Sato M, Tomoda T, Hikasa N, and Otsuki S. Inhibition of amygdaloid kindling by chronic pretreatment with cocaine or methamphetamine. Epilepsia 21: 497–507, 1980.[ISI][Medline]
Seamans JK, Durstewitz D, Christie BR, Stevens CF, and Sejnowski TJ. Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci USA 98: 301–306, 2001.
Sesack SR and Bunney BS. Pharmacological characterization of the receptor mediating electrophysiological responses to dopamine in the rat medial prefrontal cortex: A microiontophoretic study. J Pharmacol Exp Ther 249: 1323–1333, 1989.
Shu Y, Hasenstaub A, and McCormick DA. Turning on and off recurrent balanced cortical activity. Nature 423: 288–293, 2003.[CrossRef][Medline]
Siniscalchi A, Calabresi P, Mercuri NB, and Bernardi G. Epileptiform discharge induced by 4-aminopyridine in magnesium-free medium in neocortical neurons: physiological and pharmacological characterizations. Neuroscience 81: 189–197, 1997.[CrossRef][ISI][Medline]
Smialowski A. Inhibition of low calcium induced epileptiform discharges in the hippocampus by dopamine D1 receptor agonist, SKF 38393. Brain Res 528: 148–150, 1990.[CrossRef][ISI][Medline]
Starr MS. The role of dopamine in epilepsy. Synapse 22: 159–194, 1996.[CrossRef][ISI][Medline]
Starr MS and Starr BS. Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse. J Neural Transm Park Dis Dement Sect 6: 109–117, 1993a.[CrossRef][ISI][Medline]
Starr MS and Starr BS. Seizure promotion by D1 agonists does not correlate with other dopaminergic properties. J Neural Transm Park Dis 6: 27–34, 1993b.
Suppes T, Kriegstein AR, and Prince DA. The influence of dopamine on epileptiform burst activity in hippocampal pyramidal neurons. Brain Res 326: 273–280, 1985.[CrossRef][ISI][Medline]
Sutor B, Hablitz JJ, Rucker F, and Ten Bruggencate G. Spread of epileptiform activity in the immature rat neocortex studied by voltage-sensitive dyes and laser scanning microscopy. J Neurophysiol 72: 1756–1768, 1994.
Sutor B and Ten Bruggencate G. Ascorbic acid: a useful reductant to avoid oxidation of catecholamines in electrophysiological experiments in vitro? Neurosci Lett 116: 287–292, 1990.[CrossRef][ISI][Medline]
Thierry AM, Mantz J, and Glowinski J. Influence of dopaminergic and noreadrenergic afferents on their target cells in the rat medial prefrontal cortex. In: Frontal Lobe Seizures and Epilepsies, edited by Chauvel P, Delgado-Escueta AV, Halgren E, and Bancaud J. New York: Raven Press, 1992, p. 545–554.
Traub RD, Jefferys JGR, and Miles R. Analysis of the propagation of disinhibition-induced after-discharges along the guinea-pig hippocampal slice in vitro. J Physiol 472: 267–287, 1993a.
Traub RD, Jefferys JG, and Whittington MA. Enhanced NMDA conductance can account for epileptiform activity induced by low Mg2+ in the rat hippocampal slice. J Physiol 478: 379–393, 1994.[ISI][Medline]
