| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania; and 2Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut
Submitted 16 April 2006; accepted in final form 18 December 2006
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
; Glenthoj and Hemmingsen 1999; Lewis 1995; Lewis and Lieberman 2000; Miyamoto et al. 2003; Weinberger et al. 1986). Throughout the history of medicine, the pathophysiological processes underlying schizophrenia remains largely unknown. However, recent studies have proposed that the cognitive and affective impairments of this disorder may be attributed to the failure to integrate the activities of both local and distributed neural circuitry in the prefrontal cortex (PFC) (Benes 2000; Benes and Berretta 2000; Friston and Frith 1995; Grunze et al. 1996; Lewis 2000; Lidow et al. 1998; Pralong et al. 2002; Sarter et al. 2005; Selemon and Goldman-Rakic 1999; Yang and Chen 2005; Yang et al. 1999). This hypothesis is supported by the demonstrated abnormalities in the morphology and distribution of certain cortical neurons, particularly GABAergic inhibitory interneurons, in postmortem schizophrenic brains (Benes 2000; Benes and Berretta 2001; Benes et al. 1992; Hashimoto et al. 2003; Lewis et al. 2003; Volk and Lewis 2002; Woo et al. 1998). GABAergic interneurons in the cerebral cortex are known to be important for the concerted interactions between inhibitory and excitatory circuitries and constitute a critical substrate of synchronous neural activity in the brain (McBain and Fisahn 2001; Spencer et al. 2003, 2004; Whittington and Traub 2003; Whittington et al. 2000). Recent studies showed that gamma-band oscillations and synchronization, especially in the 40-Hz range, are severely disrupted in patients with schizophrenia (Calhoun et al. 2004; Lee et al. 2003a; Spencer et al. 2003, 2004; van der Stelt et al. 2004). The disrupted synchronization exhibited a decrease of gamma responses with negative symptoms or a significant increase of gamma activity with positive symptoms (Herrmann and Demiralp 2005; Lee et al. 2003a; Lee et al, 2003b).
As an atypical antipsychotic drug, clozapine has been found to be effective in alleviating positive symptoms, and possibly negative symptoms as well (Remington and Kapur 2000), of the treatment-resistant schizophrenia (Ashby and Wang 1996; Duncan et al. 1999b; Lidow and Goldman-Rakic 1994; Lieberman et al. 1989; Maguire 2002; Miyamoto et al. 2005; Safferman et al. 1994). However, the underlying mechanisms of these therapeutic actions on prefrontal cortical neuronal activity have not been fully elucidated. Previous studies suggested that clozapine enhances glutamatergic excitatory transmission in the PFC (Arvanov et al. 1997; Chen and Yang 2002; Jardemark et al. 2003; Ninan 2003) and nucleus accumbens (Wittmann et al. 2005) under conditions of disinhibition, i.e., in the presence of 
-aminobutyric acid type A (GABAA) antagonist bicuculline. This enhancement seems to require the activation of N-methyl-D-aspartate receptors (NMDARs) by various mechanisms (Arvanov et al. 1997; Chen and Yang 2002; Jardemark et al. 2003; Ninan 2003; Wittmann et al. 2005). In this study, electrophysiological recordings from acute prefrontal cortical slices were used to examine the synaptic and cellular actions of clozapine on recurrent excitation and inhibition in the PFC. These experiments were designed to address the following questions. 1) How does clozapine act on the excitatory and inhibitory synaptic transmission? 2) How does clozapine affect network activities in the PFC?
|
METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
This study used 36 ferrets from 2 to 4 mo old (Marshall Farms, North Rose, NY). The animals were cared for under National Institutes of Health animal use guidelines and the experimental protocol was approved by the Institutional Animal Care and Use Committee (IACUC) at Yale and Drexel (Gao et al. 2001). The ferrets were beheaded with a guillotine after being administered intraperitoneally (ip) with an overdose of sodium pentobarbital (100 mg/kg) to achieve deep anesthesia. The brains were quickly removed and 300-µm-thick horizontal slices containing medial PFC (mPFC, an area equivalent to rat mPFC; personal communication with Dr. Alvaro Duque) were cut on a vibratome (Vibratome, St. Louis, MO). The slice cuttings were maintained in oxygenated ice-cold Na+-free sucrose solution containing (in mM) 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 0.5 CaCl2, 7.0 MgSO4, and 213 sucrose. The slices were continuously incubated at 35°C in a Ringer solution [artificial cerebrospinal fluid (ACSF)] containing (in mM) 124 NaCl, 2.5 KCl, 1.25 NaH2PO4, 2 CaCl2, 1 MgSO4, 26 NaHCO3, and 10 dextrose, pH 7.4. The temperature of the slices in the recording chamber was kept at approximately 35–37°C. Dual or quadruple whole cell recordings were used to detect the layer 5 pyramidal-to-pyramidal unitary synaptic connections. For current clamp, the recording pipettes were filled with intracellular solution containing (in mM) 120 K-gluconate, 6 KCl, 0.5 CaCl2, 0.2 EGTA, 4 ATP-Mg, 10 Hepes, and 0.3% biocytin, with a final pH of 7.25 (Molecular Probes, Eugene, OR). Resistances of the patch pipettes ranged from 5 to 10 M
. For the voltage clamp, a Cs+- based intracellular solution (110 mM Cs-gluconate, 10 mM CsCl2, 0.2 mM EGTA, 10 mM HEPES, 1 mM ATP-Mg2+, 5 mM QX-314, and 0.3% biocytin, pH 7.3) was loaded into recording pipettes (3–6 M) to block sodium and potassium channels. To record the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), a different Cs+-based intracellular solution (134 mM CsCl2, 2 mM MgCl2, 2 mM Na2-ATP, 0.5 mM Na2GTP, 5 mM Na2-phosphocreatine, 1 mM EGTA, 10 mM HEPES, and 0.3% biocytin, pH 7.25) was used. The signals were amplified and filtered at 2 kHz with MultiClamp 700A amplifiers (Axon Instruments, Union City, CA) and acquired at sampling intervals of 20–100 µs through a DigiData 1322 interface with program pCLAMP 8.2 (Axon Instruments). The membrane potentials were not corrected for liquid junction potential. The access resistance was monitored during recordings and the data were excluded from analysis if the series resistance changed >20% from control levels (10–25 M). Synaptic strengths under conditions of control (baseline) and drug application were recorded at trial intervals of 5 s (0.2 Hz).
Pharmacological treatments
All drugs were applied to the bath through gravity. Stock solutions of all tested chemicals were stored at –70°C and were diluted to proper concentration before each experiment. The sodium channel blocker tetrodotoxin (TTX, 1 µM), the NMDA receptor antagonist D-(–)-2-amino-5-phosphonopentanoic acid (D-AP5, 50 µM), and the 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM) were purchased from Sigma–RBI (St. Louis, MO). Clozapine (0.2–10 µM, 10 mM stock in dimethyl sulfoxide), the GABAA receptor antagonist bicuculline methiodide (10 µM), and dopaminergic D4 receptor agonist PD 168077 maleate (10 µM) were obtained from Tocris Cookson (Ellisville, MO).
Data analysis
The spontaneous and miniature excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded in voltage-clamp mode were analyzed with Clampfit 9.2 (Axon Instruments). A typical EPSC/IPSC was selected to create a sample template for event detection within a data period. The frequency (event number) and amplitude of individual events were examined with Clampfit. For monosynaptic pyramidal–pyramidal connections recorded in the current-clamp mode, the amplitudes of evoked (by stimulating presynaptic cell) unitary EPSPs were measured from an average of 40–80 sweeps. To identify the synaptic mechanism, the rate of synaptic failure (percentage of stimulations that did not result in an EPSP), the coefficient of variation (CV) of individual synaptic responses and the paired-pulse ratio (PPR = 2nd EPSP/1st EPSP amplitude) between two pulses at 20 Hz (50-ms interval) were calculated. The percentage of synaptic failure to the evoked presynaptic spike was determined individually for each recording. Failure was defined as an event in which the EPSP amplitude was <1.5x noise. The mean amplitude and SD of the EPSPs were obtained from 40 to 80 successive sweeps and the CVs of EPSP amplitude for control and clozapine application conditions were computed as SD divided by mean (CV = SD/mean).
The input resistances of the tested neurons were calculated off-line from the voltage produced by negative current injection before the step currents (Fig. 1). The number of spikes was counted from recordings of control, during clozapine application, and washout period. The threshold, first spike latency, first interspike interval (1st ISI) of action potentials (APs), and the fast afterhyperpolarization (fAHP) were manually measured from the series step recordings. The amplitude and half-peak duration of APs were determined from the single AP recordings evoked by step current injection. The data were evaluated with paired t-tests and presented as means ± SE.
|
The PFC slices were immediately fixed in 4% paraformaldehyde for 
3–5 days after the physiological recordings. After thorough rinsing with 0.1 mM phosphate buffer (PBS, pH 7.4), the cortical slices were treated with 3% hydrogen peroxide for 25 min to reduce the endogenous horseradish peroxide. The ABC reactions (Vectastain ABC standard kit, Vector Laboratories, Burlingame, CA) were then conducted, followed by a Ni-DAB reaction. The slices were resectioned into 100- to 150-µm sections, mounted in 0.1 mM PB, and covered with water-soluble mounting media. Neurons were identified under a Zeiss Axioskop 2 microscope (Carl Zeiss, Oberkochen, Germany) and photographed with a Optronics digital camera (Optronics, Goleta, CA) (Gao et al. 2003).
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
, 1995). Based on these morphological and physiological characteristics, pyramidal cells and interneurons can be easily distinguished.
|
Neurons in acute brain slices are usually quiescent and stable when incubated and recorded at room temperature or, alternatively, first incubated at room temperature then recorded at higher temperature (<35°C) with regular ACSF solution. Under this condition, spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were frequently observed but exhibited asynchronous characteristics (Fig. 2A). However, when the brain slices were continuously maintained at a temperature of 35–37°C after slice cutting and perfused with a prewarmed (37°C) ACSF solution during recordings (chamber temperature maintained at about 36°C), synchronized barrages of synaptic activities could be observed in simultaneously recorded pyramidal neurons (held at –70 mV) with the Cs+-based intracellular solution (Figs. 2, B and C and 3A). The synchronous activities, which usually consisted of both individual and large complex PSC discharges (Fig. 3A), were defined as simultaneously detected oscillatory postsynaptic currents (PSCs) in multiple recorded neurons. These synchronous activities could be detected in about one third of the prefrontal slices under our recording conditions. The remaining two thirds of the cortical slices were relatively stable with very little or no synchronization, although the spontaneous activities appear to be more vigorous than those of the slices incubated at room temperature. We believe that the spontaneous synchronized activity observed here is not like a rhythmic up- and down-state (Sanchez-Vives and McCormick 2000) nor an epileptic activity (Gao and Goldman-Rakic 2006) because the amplitudes are much smaller and the durations of the PSCs are much shorter than those of the up-states and epileptic discharges observed under these two conditions. These activities may represent patterns of overexcited hypersynchrony of synaptic activities in the neuronal network. Indeed, bath perfusion of AMPA receptor blocker CNQX (20 µM) and NMDAR antagonist D-AP5 (50 µM) completely blocked the synchronized activities in all three pairs of pyramidal cells tested (Fig. 2D), suggesting the involvement of synaptic activation of glutamate receptors in the synchronized events. This proposition is supported by numerous previous studies indicating that synchronized oscillations in neocortex are generated by recurrent synaptic activity mediated by glutamate receptors (Castro-Alamancos and Rigas 2002; Fisahn et al. 1998; Sanchez-Vives and McCormick 2000).
|
|
To understand how clozapine affects the synchronized activity, pyramidal neurons from prefrontal slices that exhibited spontaneous synchronized activities were recorded before and after bath application of clozapine. Figure 3B shows an example of triple recording in which three pyramidal neurons were recorded simultaneously. Two of them (P1 and P2) were held in voltage-clamp mode (–70 mV), whereas the third one (P3) was recorded in current-clamp mode to monitor the neuronal excitability change during the clozapine application. A train of five-pulse (50-Hz, 20-ms) ISIs with positive current injection at a rate of 0.1 Hz was given to evoke action potentials in the P3 cell. Spontaneous synchronizations emerged among the pyramidal cells, although these neurons were not monosynaptically connected. In all five triplets tested, clozapine (1 µM, 3 min) effectively abolished the synchronized PSCs, although it had no significant effect on the excitabilities of pyramidal cells (see Fig. 3B, insets P3). These data also indicate that the synchronized activity is associated with the neuronal network among many neurons and, once this network activity erupted, it could not be interrupted by evoked action potentials in a single neuron. Further analysis indicated that clozapine significantly decreased PSC amplitude, especially by abolishing the synchronized PSC events (24.9 ± 0.61 pA in control vs. 16.5 ± 0.48 pA in clozapine, n = 11, P < 0.0001, Fig. 4A). In addition, clozapine also significantly reduced the frequencies of PSCs (5.55 ± 0.44 Hz in control vs. 4.35 ± 0.77 Hz in clozapine, P = 0.038, Fig. 4B). Counting the synchronous PSCs before and during clozapine application provided further evidence that the synchronized events were totally abolished by clozapine (Fig. 4, C and D). This effect was not recovered after a 10- to 15-min washout period.
|
Previous studies indicated that the synchronous activities largely depended on the network connections among the cortical neurons, especially recurrent connections in local neuronal circuitry (Singer et al. 1990; Traub et al. 2004). To examine how clozapine regulates recurrent synaptic transmission in the PFC, multiple whole cell recordings of the layer 5 pyramidal cells were performed. Clozapine consistently and significantly decreased the amplitude of unitary EPSPs in seven unidirectional pyramidal–pyramidal connections when the postsynaptic neurons were held in their resting membrane potentials (–66.3 ± 1.25 mV, n = 7, Fig. 5, A and B). The EPSP amplitude change was significant with an average reduction of 27.9% (range 13.7–52.3%, 0.88 ± 0.09 mV in the control and 0.66 ± 0.11 mV in clozapine: n = 7, P < 0.00015, Fig. 5B). The depressing effects of clozapine were partially reversed after a 10- to 15-min wash (Fig. 5B). To determine the mechanism of this depression, we examined several parameters. We found that the rates of synaptic failure were essentially unaltered (1.6% in control vs. 3.3% in clozapine, P = 0.215). The coefficients of variation of EPSP amplitude were not changed (CV, 0.28 ± 0.04 in control conditions vs. 0.33 ± 0.04 in clozapine, P = 0.192). Moreover, the paired-pulse ratios were unaffected (PPR, 0.79 ± 0.03 in control conditions vs. 0.75 ± 0.04 in clozapine, P = 0.433, Fig. 5C). All of these parameters suggest that clozapine’s action on recurrent excitatory synaptic transmission does not arise from the reduction of presynaptic glutamate release, but likely involves postsynaptic or network mechanisms. This speculation was further supported by the following experiments. When the GABAA receptor antagonist bicuculline (10 µM) was bath applied to block inhibition, the depressing effect of clozapine on recurrent excitation was completely eliminated (Fig. 6). Under this disinhibited condition, although the elicited unitary synaptic responses between two monosynaptically connected pyramidal neurons remained similar to the control, spontaneous paroxysmal "giant" EPSPs occasionally emerged, suggesting potential epileptic activities in the network of neuronal circuitry. Clozapine, in contrast, significantly enhanced the unitary EPSP amplitude by 24.4% (n = 5, P < 0.05) under this condition. This intriguing result is in agreement with numerous previous reports conducted under similar conditions (Arvanov et al. 1997; Chen and Yang 2002; Jardemark et al. 2003; Ninan 2003). The mechanism involving these differential effects of clozapine on glutamatergic EPSPs under conditions of control and of disinhibition is not clear. However, it may be attributed to the induced epileptic activities after blockade of inhibition (Keros and Hablitz 2005b). Many previous studies showed that under the disinhibited state, the ionic and receptor properties of cortical neurons are greatly changed (Avoli et al. 2002; McCormick and Contreras 2001) and thus clozapine may effect, through very different mechanisms, D1–NMDA receptor interactions, such as suggested by Chen and Yang (2002). These results, however, further support the proposition that the depressing effect of clozapine on synchronized activity is by network actions, possibly through the activation of inhibitory neurons. It also hints of the complexities of clozapine actions in the prefrontal neurons.
|
|
To further study the possibility that clozapine has direct effects on the inhibitory neurons, we examined the direct effect of clozapine on neuronal excitabilities of the prefrontal interneurons. We focused on the fast-spiking interneurons because these cells preferentially project to the soma/initial segment/proximal dendritic portions of cortical pyramidal cells and these kinds of cells constitute roughly 70% of the cortical interneurons (Kawaguchi 1995, 2001). Seventeen fast-spiking interneurons in deep layers of PFC were recorded in current-clamp mode. These neurons were initially selected under direct infrared-DIC visualization based on their multipolar morphologies and their high-frequency nonadaptive firing patterns. The identities of these neurons were confirmed by their physiologic properties, including unique action potential properties such as amplitude, half-width, and afterhyperpolarization (AHP) (Fig. 1, Table 1) (Gao et al. 2003). Most (11/17, 64.7%) of the tested cells were morphologically recovered with biocytin-labeling and all of these cells were confirmed as interneurons according to their characteristic somatodendritic morphologies (i.e., smooth and multipolar dendrites without spines). The other subtypes of interneuron, although interesting as well, were excluded from the analysis because of insufficient data to make consistent conclusions. The fast-spiking interneurons had an average resting membrane potential of –72.3 ± 1.59 mV (Table 1). At this resting potential, the input resistance averaged 170.6 ± 12.72 M. Spontaneous action potentials (spikes) were rare during the resting control condition. Injection of suprathreshold depolarizing current pulses (1,000-ms duration) evoked a train of nonadaptive high-frequency spikes with short durations (half-width of 0.58 ± 0.02 ms), followed by strong fast afterhyperpolarizations (fAHPs, average 13.2 ± 1.17 mV, Fig. 1). In contrast, pyramidal neurons (n = 6) from the same cortical area fired long-duration (half-width 1.18 ± 0.20 ms) spikes with profound adaptation, followed by significant weaker fAHPs (3.1 ± 1.01 mV, P < 0.001, Fig. 1). In addition, the spike amplitudes of interneurons were also significantly smaller (50.1 ± 4.23 mV) than those of pyramidal neurons (66.1 ± 3.48 mV, P < 0.001; Figs. 1 and 7).
|
M (12.6%, P < 0.001) by clozapine application. In addition, clozapine also significantly reduced the spike threshold (P < 0.01, Table 1) and fAHP (P < 0.0001) and shortened the first spike latency (P < 0.001) and the first ISI (P < 0.005) of the tested interneurons (Fig. 7F). In contrast, clozapine had much weaker and less-consistent effects on pyramidal cells. In three of the six layer 5 pyramidal neurons tested, clozapine induced a small hyperpolarization (–1.57 ± 0.53 mV), but in the remaining three clozapine had no clear effects, with an average reduction of –0.87 ± 0.67 mV (n = 6, P = 0.129). The average spike number decreased slightly (11.7 ± 5.47%), without statistical significance (P = 0.178, Fig. 7C). These results indicate that clozapine selectively and slightly increases the excitability of fast-spiking interneurons in the mPFC, whereas it has no clear effects on pyramidal neurons, as previously reported (Pietraszek et al. 2002). Clozapine enhances sIPSCs in pyramidal cells
To test the hypothesis that clozapine could selectively enhance action potential-dependent GABAergic inhibitory transmission, spontaneous IPSCs (sIPSCs) were recorded under voltage-clamp conditions in the presence of NMDA receptor antagonist D-AP5 (50 µM) and AMPA receptor antagonist CNQX (10 µM). To increase the driving force, the neurons were loaded with a 134 mM CsCl2 intracellular solution (see METHODS). The reversal potential of this solution in our recording condition was about +10 mV. Voltage-clamp recordings from six layer 5 pyramidal neurons (membrane potentials held at –70 mV) showed that bath application of clozapine (1–2 µM, 3–5 min) increased the frequencies (the events numbers) of sIPSCs in pyramidal cells by 22.9% (average 6.15 ± 0.76 Hz in control vs. 7.56 ± 0.71 Hz in clozapine, n = 6, P < 0.05; Fig. 8, A and B). In the presence of clozapine, there were also more large-amplitude events, presumably because of the increased spontaneous action potentials. The amplitude of averaged sIPSCs was also significantly increased by 37.2% (average 14.02 ± 0.35 pA in control vs. 19.24 ± 0.34 pA in clozapine, n = 6, P < 0.0001). Dose–response relations were not studied here because neuronal responses to different concentrations of clozapine (1–10 µM) were invariant (Fig. 7D).
|
From evidences suggesting that clozapine is an antagonist of dopamine D2 receptors, and that these receptors are mainly localized on GABAergic interneurons (Mrzljak et al. 1996), clozapine could potentially modulate the release of GABA or affect the properties of GABAA receptors. To test this hypothesis, mIPSCs were recorded in six pyramidal neurons in the presence of 1 µM TTX to block the sodium channel–mediated action potentials and 50 µM D-AP5 and 10 µM CNQX to block the ionotropic glutamate receptors. In all neurons tested, bath application of 1 µM clozapine for 3–5 min significantly increased the frequencies of mIPSCs (0.78 ± 0.14 Hz in control vs. 1.23 ± 0.24 Hz in clozapine, n = 6, P = 0.023); however, it had no clear effects on the mIPSC amplitudes (16.3 ± 0.36 pA in control vs. 16.6 ± 0.43 pA in clozapine, P = 0.153, Fig. 8, C and D) and waveforms (not shown). These data suggest that clozapine is effective in regulating GABA release from presynaptic axonal terminals of interneurons but it may not involve the gating of postsynaptic GABA receptors.
Clozapine’s effects on interneuron excitability and mIPSCs are occluded by coapplication of dopamine D4 agonist
To further elucidate the receptor specificity of clozapine actions on interneuron excitabilities, we conducted experiments to assess the potential mechanism(s) of receptor interactions. We chose to focus on dopamine D4 receptor because clozapine seems to have the highest binding affinity with this receptor and this receptor is mainly localized on the cortical GABAergic interneurons (Mrzljak et al. 1996). Figure 9 exhibits the effects of D4 agonist on interneuron excitabilities and mIPSCs on the pyramidal neurons. The spike numbers of the fast-spiking interneurons were reduced in seven of the eight cells tested with an average reduction of 18.9 ± 6.78% when PD 168077 (10 µM) was bath applied (n = 8, P = 0.035; Fig. 9, A and B). However, when clozapine (1 µM) was coapplied with PD 168077 (10 µM), the changes of spike number were variable, with four cells having no changes in spike numbers and the other four cells having either an increase (n = 2) or a decrease (n = 2) of spike numbers between 10 and 20% compared with PD 168077 application alone. The overall spike numbers were essentially unchanged in the eight interneurons tested (n = 8, P = 0.599). These results suggest that clozapine’s action on neuronal excitability was antagonized by the D4 agonist.
|
), dorsolateral septal nucleus (Asaumi et al. 2006), and hippocampus (Romo-Parra et al. 2005), but differ from the effects on postsynaptic GABAA receptors in PFC (Wang et al. 2002) and globus pallidus neurons (Shin et al. 2003). In the presence of D4 agonist, clozapine has no clear effect on either mIPSC frequency or mIPSC amplitude, suggesting that clozapine’s increase of mIPSC may be mediated by D4 receptor. |
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
The suppressive effect seemingly contradicts previous studies that suggested a NMDA-receptor–mediated enhancement of excitatory transmission in the PFC (Arvanov et al. 1997; Chen and Yang 2002; Gemperle et al. 2003; Jardemark et al. 2003; Ninan 2003) and nucleus accumbens (Wittmann et al. 2005). All of those studies, however, were conducted under conditions designed to isolate AMPA- and NMDA-receptor–mediated currents, i.e., in the presence of GABAA antagonist bicuculline. We also found that, under this same disinhibition condition, clozapine, instead of depressing recurrent excitation, significantly enhances the excitatory transmission. The mechanism involved in these differential results under normal control and disinhibition conditions remains unclear. A dopamine D1-receptor–mediated interaction with NMDA receptor was previously suggested as a possible explanation (Chen and Yang 2002) but further exploration is probably needed. The condition of the bicuculline-treated tissue may be akin to the loss of GABAergic synapses onto PFC pyramidal neurons and the associated changes in GABAA receptors presented in postmortem schizophrenic brains. The enhancement of recurrent excitation under this condition may thus be the cause of the proconvulsant effects of clozapine in human patients (Denney and Stevens 1995; Minabe et al. 1998; Stevens et al. 1996) because seizure activity is usually accompanied with impaired inhibitory functions (Avoli et al. 2002; Cossart et al. 2005; Hablitz 2004; Wong et al. 1986). Indeed, disinhibition of in vitro cortical slice by blockade of GABAA receptors could disrupt the neuronal network and induce synchronized epileptiform burst. This preparation was commonly used as a study model of epileptic activities (Avoli et al. 2002; Castro-Alamancos and Rigas 2002; Chagnac-Amitai and Connors 1989; Cohen et al. 2002; Connors 1984; Gao and Goldman-Rakic 2006; Keros and Hablitz 2005a; McCormick and Contreras 2001). Moreover, the acute suppressive effects of clozapine shown in normal brain tissue from ferret PFC are consistent with the acute sedative effect of clozapine when given to humans in both the normal control and schizophrenic patients (Ereshefsky et al. 1989; Matz et al. 1974; Ortega-Alvaro et al. 2006; Weizman and Weizman 2001). Nonetheless, whether this effect is part of the ultimate therapeutic result remains unknown.
On the other hand, the electrophysiological responses to acute clozapine may involve multiple indirect effects. A large body of neurochemical literature shows that acute clozapine can cause the release of all three major monoamines as well as amino acid transmitters in the brain (Ashby and Wang 1996; Ichikawa et al. 2002; Moghaddam and Bunney 1990; Zhang et al. 2000). For the time being, the question of whether schizophrenia is a hyperglutamatergic or hypoglutamatergic state remains unresolved. Various studies reported different results of either an increase (Daly and Moghaddam 1993), a decrease (Pietraszek et al. 2002), no change (Yamamoto and Cooperman 1994), or a chronic (9 wk) increase (Melone et al. 2001) of glutamate in the PFC after using clozapine. When clozapine is administered chronically to match the therapeutic regimens given to human schizophrenic patients, the profile of these transmitters released in the brain might be quite different. Thus the acute change in neuronal excitability and GABA transmission is likely a result of complex interactions between or among several of these transmitters, although D4 agonist exhibited partial occlusion of the acute clozapine effects on the interneuron excitabilities and the GABA release in the presynaptic terminals.
Recent studies demonstrated that interactions between inhibitory interneurons and excitatory pyramidal cells constitute a critical neural substrate for the high-frequency (15–80 Hz, beta and gamma) oscillatory activity in the cortex (McBain and Fisahn 2001; Whittington and Traub 2003; Whittington et al. 2000). Accumulating evidence bolsters the notion that such synchronous oscillations may underlie cognitive functions such as object perception, selective attention, and working memory (Calhoun et al. 2004; Lee et al. 2003a; Spencer et al. 2003, 2004; van der Stelt et al. 2004). It was hypothesized that the severely disturbed synchronous neural activity in schizophrenia, largely in the 40-Hz range gamma-band oscillation, might be attributable to the dysfunctional inhibitory networks (Calhoun et al. 2004; Lee et al. 2003a; Lewis et al. 2005; Spencer et al. 2003, 2004; van der Stelt et al. 2004; Volk and Lewis 2002). In schizophrenic patients, negative symptoms correlate with a decrease of gamma responses, whereas a significant increase in gamma amplitudes is observed during positive symptoms such as hallucinations (Herrmann and Demiralp 2005; Lee et al. 2003b).
Schizophrenia is a chronic disorder that develops gradually over time (Javitt 2004). When the disease is fully developed, obvious abnormalities in interneurons can be detected in postmortem schizophrenia brains (Addington et al. 2005; Benes et al. 1992, 1997; Gisabella et al. 2005; Hashimoto et al. 2003; Lewis et al. 2003; Volk and Lewis 2002). Clozapine was previously shown to be very effective in alleviating both the positive symptoms (e.g., hallucinations and delusions) and the negative symptoms (e.g., social and emotional withdrawal) of schizophrenia, although its effectiveness against the latter treatment-resistant psychosis remains controversial (Remington and Kapur 2000). Clozapine’s capacity to block abnormal overexcited synchronization of prefrontal neuronal network, as observed in this study, allows it to counteract the abnormal state of disrupted inhibitions that are associated with increased gamma-band oscillation in patients of schizophrenia with positive symptoms. Further supporting this hypothesis is the direct action of clozapine on the excitability of fast-spiking interneurons and its specific regulation of inhibition on pyramidal cells. Clozapine’s opposing actions on excitatory and inhibitory transmission has a synergistic effect in increasing the functionality of inhibitory circuitry of PFC. The observation of clozapine’s action in enhancing inhibitory transmission is also consistent with its putative role as an antagonist of dopamine D4 receptor and the localized D4 receptor on GABAergic interneurons (Mrzljak et al. 1996). Indeed, D4-receptor activation was found to reduce the excitability of interneurons in the prefrontal cortex and this reduction is antagonized by clozapine, consistent with previous study (Wang et al. 2002). Nonetheless, this result is not altogether congruent with other findings, suggesting that clozapine might moderately block GABAA receptors (Squires and Saederup 1998) and lower GABA release in PFC (Bourdelais and Deutch 1994). Based on the experimental results in the present study, I speculate that clozapine can readjust the balance of excitation and inhibition in cortical neuronal networks in the schizophrenic cortex by suppressing the abnormal excitatory activity exhibited in the disease (Javitt 2004). Clozapine’s acute physiologic actions in inhibitory neurons explain, at least partially, the clinical effectiveness of this antipsychotic drug on positive symptoms.
|
GRANTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: W.-J. Gao, Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129 (E-mail: wen-jun.gao{at}drexel.edu)
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
|---|
Arvanov VL, Liang X, Schwartz J, Grossman S, Wang RY. Clozapine and haloperidol modulate N-methyl-D-aspartate- and non-N-methyl-D-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283: 226–234, 1997.
Asaumi Y, Hasuo H, Akasu T. Dopamine presynaptically depresses fast inhibitory synaptic transmission via D4 receptor-protein kinase A pathway in the rat dorsolateral septal nucleus. J Neurophysiol 96: 591–601, 2006.
Ashby CR Jr, Wang RY. Pharmacological actions of the atypical antipsychotic drug clozapine: a review. Synapse 24: 349–394, 1996.[CrossRef][Web of Science][Medline]
Avoli M, D’Antuono M, Louvel J, Kohling R, Biagini G, Pumain R, D’Arcangelo G, Tancredi V. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol 68: 167–207, 2002.[CrossRef][Web of Science][Medline]
Azdad K, Piet R, Poulain DA, Oliet SH. Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic transmission in the rat supraoptic nucleus. J Neurophysiol 90: 559–565, 2003.
Benes FM. Emerging principles of altered neural circuitry in schizophrenia. Brain Res Brain Res Rev 31: 251–269, 2000.[CrossRef][Medline]
Benes FM, Berretta S. Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia. Ann NY Acad Sci 911: 293–304, 2000.[CrossRef][Web of Science][Medline]
Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25: 1–27, 2001.[CrossRef][Web of Science][Medline]
Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 12: 924–929, 1992.[Abstract]
Benes FM, Wickramasinghe R, Vincent SL, Khan Y, Todtenkopf M. Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain. Brain Res 755: 121–129, 1997.[CrossRef][Web of Science][Medline]
Bourdelais AJ, Deutch AY. The effects of haloperidol and clozapine on extracellular GABA levels in the prefrontal cortex of the rat: an in vivo microdialysis study. Cereb Cortex 4: 69–77, 1994.
Calhoun VD, Kiehl KA, Liddle PF, Pearlson GD. Aberrant localization of synchronous hemodynamic activity in auditory cortex reliably characterizes schizophrenia. Biol Psychiatry 55: 842–849, 2004.[CrossRef][Web of Science][Medline]
Castro-Alamancos MA, Rigas P. Synchronized oscillations caused by disinhibition in rodent neocortex are generated by recurrent synaptic activity mediated by AMPA receptors. J Physiol 542: 567–581, 2002.
Chagnac-Amitai Y, Connors BW. Synchronized excitation and inhibition driven by intrinsically bursting neurons in neocortex. J Neurophysiol 62: 1149–1162, 1989.
Chen L, Yang CR. Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex. J Neurophysiol 87: 2324–2336, 2002.
Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science 298: 1418–1421, 2002.
Connors BW. Initiation of synchronized neuronal bursting in neocortex. Nature 310: 685–687, 1984.[CrossRef][Medline]
Cossart R, Bernard C, Ben-Ari Y. Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies. Trends Neurosci 28: 108–115, 2005.[CrossRef][Web of Science][Medline]
Daly DA, Moghaddam B. Actions of clozapine and haloperidol on the extracellular levels of excitatory amino acids in the prefrontal cortex and striatum of conscious rats. Neurosci Lett 152: 61–64, 1993.[CrossRef][Web of Science][Medline]
Denney D, Stevens JR. Clozapine and seizures. Biol Psychiatry 37: 427–433, 1995.[CrossRef][Web of Science][Medline]
Duncan GE, Sheitman BB, Lieberman JA. An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 29: 250–264, 1999a.[CrossRef][Medline]
Duncan GE, Zorn S, Lieberman JA. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Mol Psychiatry 4: 418–428, 1999b.[CrossRef][Web of Science][Medline]
Ereshefsky L, Watanabe MD, Tran-Johnson TK. Clozapine: an atypical antipsychotic agent. Clin Pharm 8: 691–709, 1989.[Web of Science][Medline]
Fisahn A, Pike F, Buhl EH, Paulsen O. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 394: 186–189, 1998.[CrossRef][Medline]
Friston KJ, Frith CD. Schizophrenia: a disconnection syndrome? Clin Neurosci 3: 89–97, 1995.[Web of Science][Medline]
Gao WJ, Goldman-Rakic PS. NMDA receptor-mediated epileptiform persistent activity requires calcium release from intracellular stores in prefrontal neurons. Exp Neurol 197: 495–504, 2006.[CrossRef][Web of Science][Medline]
Gao WJ, Krimer LS, Goldman-Rakic PS. Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits. Proc Natl Acad Sci USA 98: 295–300, 2001.
Gao WJ, Wang Y, Goldman-Rakic PS. Dopamine modulation of perisomatic and peridendritic inhibition in prefrontal cortex. J Neurosci 23: 1622–1630, 2003.
Gemperle AY, Enz A, Pozza MF, Luthi A, Olpe HR. Effects of clozapine, haloperidol and iloperidone on neurotransmission and synaptic plasticity in prefrontal cortex and their accumulation in brain tissue: an in vitro study. Neuroscience 117: 681–695, 2003.[CrossRef][Web of Science][Medline]
Gisabella B, Bolshakov VY, Benes FM. Regulation of synaptic plasticity in a schizophrenia model. Proc Natl Acad Sci USA 102: 13301–13306, 2005.
Glenthoj BY, Hemmingsen R. Transmitter dysfunction during the process of schizophrenia. Acta Psychiatr Scand Suppl 395: 105–112, 1999.[Medline]
Grunze H, Rainnie D, Hasselmo M, Barkai E, Hearn E, McCarley R, Greene R. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16: 2034–2043, 1996.
Hablitz JJ. Regulation of circuits and excitability: implications for epileptogenesis. Epilepsy Currents 4: 151–153, 2004.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 23: 6315–6326, 2003.
Herrmann CS, Demiralp T. Human EEG gamma oscillations in neuropsychiatric disorders. Clin Neurophysiol 116: 2719–2733, 2005.[CrossRef][Web of Science][Medline]
Ichikawa J, Li Z, Dai J, Meltzer HY. Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res 956: 349–357, 2002.[CrossRef][Web of Science][Medline]
Jardemark KE, Ninan I, Liang X, Wang RY. Protein kinase C is involved in clozapine’s facilitation of N-methyl-D-aspartate- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex. Neuroscience 118: 501–512, 2003.[CrossRef][Web of Science][Medline]
Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 9: 984–997, 2004.[CrossRef][Web of Science][Medline]
Kawaguchi Y. Physiological, morphological, and histochemical characterization of three classes of interneurons in rat neostriatum. J Neurosci 13: 4908–4923, 1993.[Abstract]
Kawaguchi Y. Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J Neurosci 15: 2638–2655, 1995.[Abstract]
Kawaguchi Y. Distinct firing patterns of neuronal subtypes in cortical synchronized activities. J Neurosci 21: 7261–7272, 2001.
Keros S, Hablitz JJ. Ectopic action potential generation in cortical interneurons during synchronized GABA responses. Neuroscience 131: 833–842, 2005a.[Web of Science][Medline]
Keros S, Hablitz JJ. Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex. J Neurophysiol 94: 2073–2085, 2005b.
Lee K-H, Williams LM, Breakspear M, Gordon E. Synchronous gamma activity: a review and contribution to an integrative neuroscience model of schizophrenia. Brain Res Rev 41: 57–78, 2003a.[CrossRef][Medline]
Lee KH, Williams LM, Haig A, Gordon E. Gamma (40 Hz) phase synchronicity and symptom dimensions in schizophrenia. Cognit Neuropsychiatry 8: 57–71, 2003b.[Medline]
Lewis DA. Neural circuitry of the prefrontal cortex in schizophrenia. Arch Gen Psychiatry 52: 269–273; discussion 267–268, 1995.
Lewis DA. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res Brain Res Rev 31: 270–276, 2000.[CrossRef][Medline]
Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6: 312–324, 2005.[CrossRef][Web of Science][Medline]
Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 28: 325–334, 2000.[CrossRef][Web of Science][Medline]
Lewis DA, Volk DW, Hashimoto T. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology (Berl) 174: 143–150, 2003.
Lidow MS, Goldman-Rakic PS. A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex. Proc Natl Acad Sci USA 91: 4353–4356, 1994.
Lidow MS, Williams GV, Goldman-Rakic PS. The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 19: 136–140, 1998.[CrossRef][Medline]
Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry 50: 329–338, 1989.[Web of Science][Medline]
Maguire GA. Comprehensive understanding of schizophrenia and its treatment. Am J Health Syst Pharm 59: S4–S11, 2002.
Matz R, Rick W, Thompson H, Gershon S. Clozapine—a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res Clin Exp 16: 687–695, 1974.[Web of Science][Medline]
McBain CJ, Fisahn A. Interneurons unbound. Nat Rev Neurosci 2: 11–23, 2001.[Web of Science][Medline]
McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 63: 815–846, 2001.[CrossRef][Web of Science][Medline]
Melone M, Vitellaro-Zuccarello L, Vallejo-Illarramendi A, Perez-Samartin A, Matute C, Cozzi A, Pellegrini-Giampietro DE, Rothstein JD, Conti F. The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. Mol Psychiatry 6: 380–386, 2001.[CrossRef][Web of Science][Medline]
Minabe Y, Watanabe K, Nishimura T, Ashby CR Jr. Acute and chronic administration of clozapine produces greater proconvulsant actions than haloperidol on focal hippocampal seizures in freely moving rats. Synapse 29: 272–278, 1998.[CrossRef][Web of Science][Medline]
Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10: 79–104, 2005.[CrossRef][Web of Science][Medline]
Miyamoto S, LaMantia AS, Duncan GE, Sullivan P, Gilmore JH, Lieberman JA. Recent advances in the neurobiology of schizophrenia. Mol Interv 3: 27–39, 2003.
Moghaddam B, Bunney BS. Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54: 1755–1760, 1990.[Web of Science][Medline]
Mrzljak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS. Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 381: 245–248, 1996.[CrossRef][Medline]
Ninan I, Jardemark KE, Wang RY. Differential effects of atypical and typical antipsychotic drugs on N-methyl-D-aspartate- and electrically evoked responses in the pyramidal cells of the rat medial prefrontal cortex. Synapse 48: 66–79, 2003.[CrossRef][Web of Science][Medline]
Ortega-Alvaro A, Gibert-Rahola J, Mico JA. Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 30: 104–111, 2006.[CrossRef][Medline]
Pietraszek M, Go
embiowska K, Bijak M, Ossowska K, Wolfarth S. Differential effects of chronic haloperidol and clozapine administration on glutamatergic transmission in the fronto-parietal cortex in rats: microdialysis and electrophysiological studies. Naunyn-Schmiedeberg’s Arch Pharmacol 366: 417–424, 2002.[CrossRef][Web of Science][Medline]
Pralong E, Magistretti P, Stoop R. Cellular perspectives on the glutamate-monoamine interactions in limbic lobe structures and their relevance for some psychiatric disorders. Prog Neurobiol 67: 173–202, 2002.[CrossRef][Web of Science][Medline]
Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology 148: 3–15, 2000.[CrossRef][Medline]
Romo-Parra H, Aceves J, Gutierrez R. Tonic modulation of inhibition by dopamine D4 receptors in the rat hippocampus. Hippocampus 15: 254–259, 2005.[CrossRef][Web of Science][Medline]
Safferman AZ, Kane JM, Aronowitz JS, Gordon MF, Pollack S, Lieberman JA. The use of clozapine in neurologic disorders. J Clin Psychiatry 55, Suppl. B: 98–101, 1994.[Web of Science][Medline]
Sanchez-Vives MV, McCormick DA. Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat Neurosci 3: 1027–1034, 2000.[CrossRef][Web of Science][Medline]
Sarter M, Nelson CL, Bruno JP. Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 31: 117–138, 2005.
Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45: 17–25, 1999.[CrossRef][Web of Science][Medline]
Shin R-M, Masuda M, Miura M, Sano H, Shirasawa T, Song W-J, Kobayashi K, Aosaki T. Dopamine D4 receptor-induced postsynaptic inhibition of GABAergic currents in mouse globus pallidus neurons. J Neurosci 23: 11662–11672, 2003.
Singer W, Gray C, Engel A, Konig P, Artola A, Brocher S. Formation of cortical cell assemblies. Cold Spring Harb Symp Quant Biol 55: 939–952, 1990.
Spencer KM, Nestor PG, Niznikiewicz MA, Salisbury DF, Shenton ME, McCarley RW. Abnormal neural synchrony in schizophrenia. J Neurosci 23: 7407–7411, 2003.
Spencer KM, Nestor PG, Perlmutter R, Niznikiewicz MA, Klump MC, Frumin M, Shenton ME, McCarley RW. Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc Natl Acad Sci USA 101: 17288–17293, 2004.
Squires RF, Saederup E. Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same "core" fraction of GABA(A) receptors. Neurochem Res 23: 1283–1290, 1998.[CrossRef][Web of Science][Medline]
Stevens JR, Denney D, Szot P. Kindling with clozapine: behavioral and molecular consequences. Epilepsy Res 26: 295–304, 1996.[CrossRef][Web of Science][Medline]
Traub RD, Bibbig A, LeBeau FEN, Buhl EH, Whittington MA. Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro. Annu Rev Neurosci 27: 247–278, 2004.[CrossRef][Web of Science][Medline]
van der Stelt O, Belger A, Lieberman JA. Macroscopic fast neuronal oscillations and synchrony in schizophrenia. Proc Natl Acad Sci USA 101: 17567–17568, 2004.
Volk DW, Lewis DA. Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction. Physiol Behav 77: 501–505, 2002.[CrossRef][Medline]
Wang X, Zhong P, Yan Z. Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci 22: 9185–9193, 2002.
Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 43: 114–124, 1986.
Weizman R, Weizman A. Use of atypical antipsychotics in mood disorders. Curr Opin Investig Drugs 2: 940–945, 2001.[Medline]
Whittington MA, Faulkner HJ, Doheny HC, Traub RD. Neuronal fast oscillations as a target site for psychoactive drugs. Pharmacol Ther 86: 171–190, 2000.[CrossRef][Web of Science][Medline]
Whittington MA, Traub RD. Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26: 676–682, 2003.[CrossRef][Web of Science][Medline]
Wittmann M, Marino MJ, Henze DA, Seabrook GR, Conn PJ. Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases. J Pharmacol Exp Ther 313: 594–603, 2005.
Wong RK, Traub RD, Miles R. Cellular basis of neuronal synchrony in epilepsy. Adv Neurol 44: 583–592, 1986.[Medline]
Woo TU, Whitehead RE, Melchitzky DS, Lewis DA. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci USA 95: 5341–5346, 1998.
Yamamoto BK, Cooperman MA. Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14: 4159–4166, 1994.[Abstract]
Yang CR, Chen L. Targeting prefrontal cortical dopamine d1 and N-methyl-d-aspartate receptor interactions in schizophrenia treatment. Neuroscientist 11: 452–470, 2005.
Yang CR, Seamans JK, Gorelova N. Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex. Neuropsychopharmacology 21: 161–194, 1999.[CrossRef][Web of Science][Medline]
Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23: 250–262, 2000.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  H.-S. Huang, A. Matevossian, C. Whittle, S. Y. Kim, A. Schumacher, S. P. Baker, and S. Akbarian Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters J. Neurosci., October 17, 2007; 27(42): 11254 - 11262. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
