| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1Department of Neurobiology and Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama; and 2Institute of Physiology, University of Munich, Munich, Germany
Submitted 19 August 2005; accepted in final form 30 November 2005
 |
ABSTRACT |
|---|
|
-aminobutyric acid (GABAA) receptor-dependent synchronized activity in interneurons. This results in waves of activity propagating through upper cortical layers. Because interneurons in the neocortex are excited by nicotinic acetylcholine receptor (nAChR) agonists, ACh may influence synchronization of these local neocortical interneuronal networks. To study this possibility, we have used voltage-sensitive dye imaging using the fluorescent dye RH 414 (30 µM) in rat neocortical slices. Recordings were obtained in the presence of 4-AP (100 µM) and the EAA receptor antagonists D-2-amino-5-phosphonvaleric acid (20 µM) and 6-cyano-7-nitro-quinoxaline-2,3-dione (10 µM). In response to intracortical stimulation, localized or propagated activity restricted to upper cortical layers was seen. Bath application of the ACh esterase inhibitor neostigmine (10 µM) and the nAChR agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP; 10 µM) increased the response amplitude, the extent of spread, and the duration of this activity. These changes were seen in 13 of 16 slices tested with neostigmine (10 µM) and 4 of 7 slices tested with DMPP (10 µM). Application of the muscarinic AChR antagonist atropine (1 µM) did not block the enhancement of activity by neostigmine (n = 7). Application of dihydro-
-erythroidine (10 µM), known, at this concentration, to selectively antagonize 
42-like nAChRs, blocked the effect of neostigmine (n = 5). The selective 7-like nAChR antagonist methyllycaconitine (50 nM) was ineffective (n = 5). These results suggest that activation of 42-like nAChRs by endogenously released ACh can enhance synchronized activity in local neocortical inhibitory networks. |
|
INTRODUCTION |
|---|
|
). ACh acts via two different types of receptors: muscarinic and nicotinic. Muscarinic receptors are metabotropic and thought to predominantly mediate postsynaptic effects of ACh in the CNS (McCormick and Prince 1986), although evidence exists for a presynaptic function (Sheridan and Sutor 1990). Nicotinic ACh receptors (nAChRs) are ligand-gated ion channels that mediate fast excitatory synaptic transmission in the peripheral nervous system. Presence of nAChRs has been detected in different brain regions including the neocortex. Both homo- and heteromeric receptors exist in the brain (Le Novere et al. 2002; Sargent 1993; Wada et al. 1989). Heteromeric 42 and homomeric 7 nAChRs are the most abundant and widely expressed nAChRs (Wada et al. 1989). nAChRs in the CNS are important for neuronal development, attention, learning and memory, nocioception, and cognition (for review, see: Jones et al. 1999; Levin 2002; Picciotto et al. 2000; Role and Berg 1996). Neuronal nAChRs play a role in the pathogenesis of brain disorders such as epilepsy, schizophrenia, Alzheimer's disease, and Parkinson's disease (for review, see: Lena and Changeux 1997; Lucas-Meunier et al. 2003; Newhouse et al. 1997; Raggenbass and Bertrand 2002). Linking of human autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) to a mutation in the nAChR 4 subunit (Steinlein et al. 1995, 1997) underscores the importance of nAChRs in modulation of circuit excitability in the neocortex.
Presynaptic modulation of glutamate release by nAChRs has been demonstrated in the olfactory bulb (Alkondon et al. 1996), the hippocampus (Gray et al. 1996; Radcliffe and Dani 1998), and the prefrontal cortex (Gioanni et al. 1999). Increases in the release of dopamine, norepinephrine, and serotonin in response to nicotinic stimulation in prefrontal cortex have also been reported (Rao et al. 2003). Studies in rat hippocampal and human neocortical slices suggest that nAChRs can trigger -aminobutyric acid (GABA) release from interneurons as well (Albuquerque et al. 2000; Alkondon et al. 1997, 1999). Glutamatergic neurotransmission is enhanced by nicotinic agonists in the nucleus accumbens, whereas muscarinic agonists have an opposite effect (Zhang and Warren 2002). Increases and decreases in excitatory postsynaptic currents (EPSCs) mediated by nicotinic and muscarinic agonists respectively have also been reported in layers II/III pyramidal neurons of rat prefrontal cortex (PFC) (Vidal and Changeux 1989, 1993). Interneurons can be directly excited by nAChR activation in hippocampus (Frazier et al. 1998; Jones and Yakel 1997) and neocortex (Christophe et al. 2002; Porter et al. 1999; Xiang et al. 1998). The highest laminar densities of cholinergic axons and varicosities are found in layer I of the neocortex (Mechawar et al. 2000), which contains sparsely distributed nonpyramidal neurons (Zhou and Hablitz 1996). Such dense cholinergic innervation of layer I suggests that this layer may be a major site of cholinergic modulation of neocortical networks.
In the presence of AMPA and N-methyl-D-aspartate (NMDA), receptor antagonists to block EAA-mediated synaptic transmission, 4-aminopyridine (4-AP) produces depolarizing responses in the neocortex (Aram et al. 1991; Avoli et al. 1994; Benardo 1997). Such responses are thought to arise from synchronized activity in interneurons mediated by GABAA receptors and are referred to as GABA waves. Electrophysiological (Yang and Benardo 2002) and voltage-sensitive dye imaging experiments (DeFazio and Hablitz 2005) suggest that only the superficial layers of the cortex support these responses. Because interneurons in the neocortex can be excited via activation of nAChRs (Christophe et al. 2002; Porter et al. 1999; Xiang et al. 1998), ACh may have a role in synchronizing interneuron activity in the neocortex. Using voltage-sensitive dye imaging, we show that endogenous ACh can increase synchronized interneuron activity in local inhibitory circuits in rat prefrontal cortex. This action of ACh requires activation of 42-like nAChRs. A preliminary account of these findings has been published in an abstract form (Bandyopadhyay et al. 2004).
|
|
METHODS |
|---|
|
Brain slices from 20- to 42-day-old Sprague-Dawley rats were used. Rats were housed and handled according to the guidelines of the National Institutes of Health Committee on Laboratory Animal Resources. Prior approval from the UAB Institutional Animal Care and Use Committee was obtained for all experimental protocols. Rats were decapitated under ketamine anesthesia (100 mg/kg ip). After quick dissection, rat brains were placed in ice-cold low-calcium saline containing (in mM) 125 NaCl, 3.5 KCl, 26 NaHCO3, 10 D-glucose, 3 MgCl2, and 1 CaCl2. Coronal brain slices (300 µm thick) containing the prefrontal cortex were cut using a Vibratome (Ted Pella, Redding, CA), incubated in recording saline containing (in mM) 125 NaCl, 3.5 KCl, 26 NaHCO3, 10 D-glucose, 2.5 CaCl2, and 1.3 MgCl2) for 45 min at 37°C, and then kept at room temperature until recording. The solution was bubbled with a gas mixture containing 95% O2-5% CO2 to maintain pH around 7.4. Each slice was transferred before recording to a second incubation chamber where they were incubated at room temperature for 30 min in recording saline containing 4-AP (100 µM) and the EAA receptor antagonists D-2-amino-5-phosphonvaleric acid (D-APV; 20 µM) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 10 µM). Slices were subsequently transferred to a recording chamber continuously perfused (3 ml/min) with recording saline (bubbled with 95% O2-5% CO2 gas mixture) containing 4-AP (100 µM), D-APV (20 µM), and CNQX (10 µM).
Electrophysiological and optical recordings
Neurons in slices were visualized using a Zeiss Axioskop FS (Carl Zeiss, Thornwood, NY) microscope equipped with Nomarski optics, a x40 water-immersion lens and infrared illumination. Layer I neurons were identified by their subpial location. Biocytin labeling was used to confirm neuronal location and identity. Whole cell current-clamp recordings were obtained as described previously (Bandyopadhyay et al. 2005). Patch electrodes were pulled from borosilicate glass capillary tubes and filled with intracellular solution containing (in mM) 125 K-gluconate, 10 KCl, 10 HEPES, 2 Mg-ATP, 0.2 Na-GTP, and 0.5 EGTA (pH = 7.3; osmolarity = 290 mosM). When filled with this intracellular solution, the patch electrodes had resistances between 3 and 5 M
. Series resistance was <20 M in all experiments and was not compensated. Recordings were discontinued if series resistance increased by >20%. The excitatory amino acid (EAA) receptor antagonists D-APV (20 µM) and CNQX (10 µM) were bath applied to block NMDA and AMPA receptor mediated EPSPs. Bath application of 4-AP (100 µM) in the presence of the EAA antagonists was used to unmask GABA waves in the slice. Square wave current pulses (100–400 µA in amplitude and 100 µs in duration) delivered at a frequency of 1/min via a bipolar stimulating electrode positioned in middle cortical layers were used to evoke GABA responses. All recordings were done at 32 ± 1°C. Signals were recorded using a MultiClamp 700A amplifier (Molecular Devices, Sunnyvale, CA), filtered at 5 kHz and digitized at 10–20 kHz via a Digidata 1200B interface (Molecular Devices).
The voltage-sensitive fluorescent dye {N-[3-(triethylammonium)propyl]-4-[4-(p-diethylaminophenyl)butadienyl]pyridinium dibromide; RH 414; Molecular Probes, Eugene, OR} (Grinvald et al. 1988) was used for the imaging experiments. Slices were incubated in recording saline containing (in µM) 30 RH 414, 100 4-AP, 20 D-APV, and10 CNQX for 45–60 min at room temperature. Individual slices were then placed in the recording chamber on the stage of the microscope (Axiovert 135TV, Carl Zeiss) used for optical recording. The recording chamber was continuously perfused with recording saline (3 ml/min) containing 4-AP (100 µM), D-APV (20 µM), and CNQX (10 µM). Slices were allowed to sit in the recording chamber for 
30 min prior to recording to wash out excess dye. A bipolar stimulating electrode positioned in middle cortical layers was used to evoke activity in the slices. The frequency of stimulation was 1/min. Local field potentials were recorded with an extracellular glass electrode (filled with extracellular saline) in superficial cortical layers. All imaging experiments were performed at 32 ± 1°C. A photodiode array containing 464 diodes arranged in a hexagonal fashion (Neuroplex, Red Shirt Imaging, Fairfield, CT) was used to detect changes in fluorescence due to activity in the brain slices, as described previously (Bandyopadhyay et al. 2005). The resting light intensity measured for each detector was used to normalize fluorescence measurements. Correction for dye bleaching was done using measurements taken in the absence of stimulation. All optical signals are represented as changes in fluorescence over resting fluorescence (
F/F where F is the resting fluorescence and F is the change in fluorescence with activity). The dye RH 414 responds to membrane depolarization with a decrease in fluorescence. Decreases in fluorescence are plotted as upward deflections in all figures. Pseudocolor images were created from the data for visualizing spatiotemporal patterns of activity in the slice. A fixed pseudocolor scale was used for all frames in a given figure. Slices were stained with cresyl violet to allow identification of the relationship of the optical signals with the cortical laminae.
Drug application
Neostigmine, an ACh esterase inhibitor, was used to decrease the degradation of endogenous ACh released on electrical stimulation in the slice. 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) was used as a selective nAChR agonist, whereas dihydro--erythroidine (DHE) and methyllycaconitine (MLA) were used as nicotinic antagonists. All the drugs were applied by adding to the bath solution. After recording control responses, neostigmine or DMPP were bath applied for 10–15 min. In all experiments in which antagonists were tested, the antagonists were present in both control and agonist-containing solutions unless mentioned otherwise. Drugs were stored in frozen stock solutions and dissolved in the saline prior to each experiment. 4-AP, DMPP, MLA, neostigmine, and tetrodotoxin were purchased from Sigma (St. Louis, MO) and D-APV and CNQX from Tocris Cookson (Ellisville, MO).
Data analysis and statistics
Data from imaging experiments were analyzed as described previously (Bandyopadhyay et al. 2005). A region of interest (ROI) in the control recording was first chosen. The ROI included photodiodes detecting visually obvious activity along with surrounding diodes detecting no apparent activity. The baseline noise level was calculated as the average of peak signal amplitudes (peak F/F) of five diodes outside the ROI with no obvious signal. Peak signal amplitude above twice that of the baseline noise was chosen as the threshold value for activity. Diodes in the ROI showing peak signal amplitudes above the threshold were selected for analysis. The sum of the peak signal amplitudes of these diodes are referred to as the "peak activity." The estimate of the duration of activity was obtained from the time interval between the first and the last frames of an acquisition showing activity. These parameters were measured in images taken before and 10 min after drug application in all the imaging experiments.
Student's t-test was used for statistical comparison (OriginPro 7.0 software) before and after drug application. P < 0.05 was considered significant. Data are expressed as means ± SE.
|
|
RESULTS |
|---|
|
Whole cell current-clamp recordings were obtained from layer I neurons (n = 5) in the PFC. Interneurons were identified as fast spiking cells based on action potential width and response to depolarizing current pulses. Biocytin labeling confirmed location in layer I. Intracortical stimulation was used to evoke activity in the presence of D-APV (20 µM) and CNQX (10 µM) to block NMDA and AMPA receptor-mediated excitation and 4-AP (100 µM) to enhance transmitter release in response to stimulation. Depolarizing responses with superimposed action potentials of variable amplitudes were observed at resting membrane potentials (–73 ± 2 mV, n = 5). Response amplitudes increased when cells were hyperpolarized by current injection (Fig. 1A, top trace). Such responses are known to be mediated by GABAA receptors (Aram et al. 1991; Benardo 1997). Bath application of bicuculline (10 µM) blocked the response (n = 5, results not shown). Whole cell responses were similar in time course to the local field potentials recorded from the superficial layers of the slice (Fig. 1A, middle trace) as well as to the optical signals obtained from neocortical slices imaged with the voltage-sensitive dye RH 414 (Fig. 1A, bottom trace). Voltage-sensitive dye imaging has the advantage of detecting activity from a large area of a brain slice suitable for studying activity in a network of neurons. Therefore imaging with the voltage-sensitive dye RH 414 was utilized to study the effect of stimulus-evoked release of endogenous ACh on spatiotemporal pattern of GABA waves in the neocortex.
|
For imaging, a hexagonal photodiode array containing 464 diodes was utilized. A x5 objective was used to cover a large area of the slice (3.5 x 3.5 mm) reaching from the pia to the white matter. Intracortical stimulation in the presence of D-APV (20 µM), CNQX (10 µM), and 4-AP (100 µM) was used to evoke GABA waves. Figure 1B shows a pseudocolor spatial map of such a response superimposed on the cresyl violet-stained image of the slice. The activity was more intense in the upper layers of the neocortex and the spread of activity was more marked in the horizontal direction as described previously (DeFazio and Hablitz 2005). The activity was abolished by tetrodotoxin (1 µM) (n = 4, results not shown) indicating a dependence on action-potential-dependent transmitter release.
Stimulus-evoked release of endogenous ACh enhances GABA waves in the neocortex
The spatiotemporal distribution of GABA wave activity is shown in Fig. 2A. Pseudocolor images in each panel show the spatial distribution of dye signals (F/F) at a given point in time. Pseudocolor scaling was the same for all frames. Warm colors represent larger-amplitude dye signals, i.e., high levels of activity. The pial surface is up in each panel. The first panel is prior to the stimulus and additional panels are shown at 50-ms intervals. The control images acquired using weak intracortical stimulation show an area of activity that appeared near the stimulating electrode and persisted for 523 ± 26 ms (n = 13; Fig. 2A). The largest-amplitude dye signals were observed in the superficial layers of the cortex, and the signal amplitudes gradually decreased in the deeper layers. The activity spread horizontally through the neocortex in both directions. The extent of spread was variable with 54% of the slices showing spread of activity beyond the imaged area. Similar patterns of activity were seen in experiments (n = 10) with more mature rats (4–6 wk old). In these older animals, 60% of the slices had widespread activity extending beyond the imaged area.
|
), dorsal cochlear nucleus (Chen et al. 1998), and nucleus ambiguous (Wang et al. 2003). After application of neostigmine (10 µM) for 10 min, the evoked responses increased in amplitude, persisted for a longer period of time (685 ± 31 ms; n = 13; P < 0.05) and spread horizontally through the upper layers of the cortex out of the imaging area (Fig. 2B). The increase in amplitude of the dye signals following application of neostigmine is evident in the superimposed dye signals from three different diodes (Fig. 2C). Peak activity levels (see METHODS) were increased from 0.30 ± 0.03 in controls to 0.43 ± 0.04 (n = 13; P < 0.05) after neostigmine application. Thirteen of 16 slices tested with neostigmine (10 µM) showed a similar pattern of enhancement. These data suggest that endogenously released ACh can enhance the amplitude, duration, and spread of depolarizing GABA waves in the neocortex in vitro. Effect of ACh on GABA waves is mediated by nAChRs
To determine the cholinergic receptor type (muscarinic or nicotinic) involved in the enhancement of GABA waves in the neocortex, we tested the effect of the muscarinic ACh receptor antagonist atropine (1 µM). The enhancement by neostigmine (10 µM) of stimulus-evoked GABA waves was not blocked by atropine (1 µM; Fig. 3). In the presence of atropine (1 µM), bath application of neostigmine led to an enhancement of activity (n = 7) as seen in experiments without atropine. Peak activity level was significantly higher (0.54 ± 0.09 vs. 0.85 ± 0.20; n = 7; P < 0.05) and duration of activity was significantly prolonged (497 ± 49 vs. 677 ± 25 ms; n = 7; P < 0.05) when neostigmine (10 µM) was applied in continued presence of atropine (1 µM; Fig. 5).
|
|
Cholinergic enhancement of GABA waves require 42-like nAChRs
Homomeric 7-like and heteromeric 42-like nAChRs are the predominant nicotinic receptor subtypes in the neocortex. To determine the nAChR subtype mediating the effect of ACh observed, we used the nicotinic antagonists MLA and DHE known to selectively block 7-like and 42-like nAChRs, respectively. The 7 subunit-selective nAChR antagonist MLA (50 nM) was not effective in blocking the neostigmine effect (Fig. 5). Significant increases in peak activity (0.27 ± 0.01 vs. 0.34 ± 0.01; n = 5; P < 0.05) and duration of activity (420 ± 49 vs. 587 ± 17 ms; n = 5; P < 0.05) were still observed when neostigmine (10 µM) was applied in presence of MLA (50 nM). DHE (10 µM), at this concentration known to selectively antagonize 42-like nAChRs (Alkondon and Albuquerque 2001; Alkondon et al. 1999), prevented the neostigmine-induced enhancement of GABA waves (Fig. 4). No significant changes in peak activity (0.37 ± 0.04 vs. 0.35 ± 0.04; n = 5; P > 0.05) and duration of activity (517 ± 59 vs. 484 ± 64 ms; n = 5; P > 0.05) were seen (Fig. 5) when neostigmine (10 µM) was applied in presence of DHE (10 µM).
|
7-like and 42-like nAChRs on GABA waves were examined without application of neostigmine. MLA (50 nM) did not have any significant effect on amplitude (peak activity: 0.24 ± 0.03 vs. 0.23 ± 0.03; n = 5; P > 0.05) or duration (326 ± 55 vs. 339 ± 61 ms; n = 5; P > 0.05) of GABA waves evoked by intracortical stimulation under this condition (Fig. 5). On the other hand, application of DHE (10 µM) resulted in a significant decrease in both peak activity (0.52 ± 0.11 vs. 0.46 ± 0.10; n = 5; P < 0.05) and duration (443 ± 84 vs. 345 ± 73 ms; n = 5; P < 0.05) of evoked GABA waves (Fig. 5). |
|
DISCUSSION |
|---|
|
42-like nAChRs, can enhance synchronization of interneurons in the neocortex. Neocortical GABA waves
Evidence for GABAA receptor-mediated synchronous activity in interneurons was first reported by Aram et al. (1991) after application of the convulsant agent 4-AP in the presence of EAA receptor antagonists. Similar events have also been described in human neocortical slices (Avoli et al. 1994). Imaging with voltage-sensitive dyes has shown that these discharges can give rise to widespread depolarization in slices from hippocampus (Sinha and Saggau 2001) and neocortex (DeFazio and Hablitz 2005). GABAA receptor-dependent depolarizing responses have been recorded from both pyramidal neurons and interneurons in rat neocortex (DeFazio and Hablitz 2005; Keros and Hablitz 2005). Ectopic action potentials (abruptly arising spikes of variable amplitudes occurring below normal spike threshold) during depolarizing GABA responses are more likely to occur in layer I interneurons and may play a role in synchronizing discharge from these interneurons (Benardo 1997; Keros and Hablitz 2005). Synaptic (Tamas et al. 1998; Zhou and Hablitz 1996) and electrical (Chu et al. 2003; Draguhn et al. 1998; Galaretta and Hestrin 1999) coupling of neocortical interneurons facilitates such synchronization. We show here that GABAA receptor-dependent depolarizing responses associated with action potentials of variable amplitudes can be recorded from layer I interneurons. GABA waves in whole cell recordings correlate well with the local field potentials and the optical signals recorded from individual diodes in voltage-sensitive dye imaging experiments, suggesting that such imaging can be a powerful tool to study spatiotemporal pattern of synchronized interneuron activity in brain slices.
One possible mechanism for GABA waves in mature cortex may be elevation of extracellular potassium ions leading to intracellular chloride accumulation due to influx of chloride via potassium-coupled chloride transporters (DeFazio and Hablitz 2005; DeFazio et al. 2000). Elevations of extracellular potassium during GABA waves (Louvel et al. 2001) and enhancement of GABAergic responses by 4-AP occur preferentially in upper cortical layers (Barkai et al. 1995; Yang and Benardo 2002). Elevations in extracellular potassium could enhance ACh release from cholinergic terminals.
Cholinergic modulation of synaptic transmission in neocortex
Although nAChRs are known to mediate fast excitatory synaptic transmission in the hippocampus (Alkondon et al. 1998; Frazier et al. 1998; Jones and Yakel 1997) and the neocortex (Chu et al. 2000; Roerig et al. 1997), the major role of ACh in the brain appears to be modulatory. Both 42-like and 7-like nAChRs have been shown to modulate glutamate mediated synaptic transmission (Gioanni et al. 1999; Gray et al. 1996; McGehee et al. 1995; Radcliffe and Dani 1998) and GABA (Alkondon et al. 1997, 1999). Glutamate release from thalamocortical terminals onto pyramidal cells in rat prefrontal cortex has been shown to be increased by presynaptic nAChR activation (Gioanni et al. 1999; Lambe et al. 2003; Vidal and Changeux 1989, 1993); 42-like nAChRs have been implicated based on pharmacological sensitivity and the fact that the effect is absent in transgenic mice lacking 2 subunits (Lambe et al. 2003). Interneurons in rat prefrontal cortex can be directly excited by stimulation of postsynaptic 42-like and 7-like nAChRs (Christophe et al. 2002; Porter et al. 1999). Such excitation is confined to a subset of interneurons in deeper (II-V) layers (Porter et al. 1999), whereas all types of interneurons in layer I are excited (Christophe et al. 2002). Human neocortical interneurons also have functional nAChRs and stimulation of presynaptic 42-like nAChRs results in synchronized GABA release from several GABAergic synapses (Alkondon et al. 2000). Synchronization of GABA release from interneurons in upper layers of prefrontal cortex may underlie the facilitatory effect of neostigmine on GABA waves observed in the present imaging experiments. Because neostigmine blocks degradation of ACh, its effect is usually attributed to a prolonged action of ACh. Although ACh esterase inhibitors can act as allosteric modulators of nAChRs (Maelicke et al. 1993; Pereira et al. 1994; Schrattenholz et al. 1996; Storch et al. 1995), such modulation is insensitive to blockade by competitive nAChR antagonists like DHE (Pereira et al. 1994; Storch et al. 1995). A direct effect of neostigmine on nAChRs can be excluded because DHE (10 µM) blocked neostigmine-induced enhancement of evoked GABA waves. DHE (10 µM) also depressed GABA waves evoked in the absence of neostigmine. Direct inhibitory effects of neostigmine on nAChRs, if present, would have attenuated the ACh-induced enhancement of GABA waves. These observations lend support to the fact that endogenously released ACh is involved in the enhancement of evoked GABA waves seen in this study.
The cholinergic enhancement of GABA waves was mediated by nAChRs because the effect was mimicked by the nAChR agonist DMPP (10 µM). The DMPP-induced enhancement could be blocked by the nicotinic antagonist DHE (10 µM) but not by the muscarinic antagonist atropine (1 µM). The 42 subtype of nAChRs was involved because the nAChR antagonist DHE (10 µM) predominantly blocks 42-like nAChRs (Alkondon and Albuquerque 2001; Alkondon et al. 1999), and the nicotinic effect was insensitive to blockade by the antagonist MLA (50 nM) selective for 7-like nAChRs (Alkondon et al. 1992).
ACh, synchronized interneuron activity, and network oscillations
Networks of GABAergic interneurons can generate synchronous oscillations (Blatow et al. 2003; Buzsaki and Chrobak 1995; Fisahn et al. 1998). Synchronization of a mutually interconnected network of interneurons can occur via recurrent collaterals as a result of depolarizations mediated by synaptically activated GABAA receptors as well as electrical coupling between the interneurons (Beierlein et al. 2000; Benardo 1997; Galaretta and Hestrin 1999; Michelson and Wong 1994; Skinner et al. 1999). Oscillations arising out of synchronized interneuron activity may provide a temporal structure for correlated firing of a group of neurons that encodes information in a cortical circuit and phase their firing activity. GABAergic interneurons in hippocampus have the ability to phase spontaneous firing and subthreshold oscillations in pyramidal cells at theta frequencies (Cobb et al. 1995). Association of hippocampal theta rhythm with exploratory behavior in rodents suggests its involvement in spatial learning and memory (Bland 1986; Huerta and Lisman 1993; Larson et al. 1986). Theta oscillations have also been reported in the neocortex (Bao and Wu 2003; Blatow et al. 2003; Raghavachari et al. 2001; Sarnthein et al. 1998), and bursting discharges from cholinergic basal forebrain neurons have been shown to be associated with theta oscillations (Lee et al. 2005). Cholinergic induction of theta oscillations has been reported in a chemically and electrically coupled network of interneurons in mouse neocortex (Blatow et al. 2003). Thus cholinergic enhancement of synchronized interneuron activity observed in this study may have a role in theta frequency oscillations in rat neocortex.
|
|
GRANTS |
|---|
|
|
|
ACKNOWLEDGMENTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: J. J. Hablitz, Dept. of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 (E-mail: hablitz{at}nrc.uab.edu)
|
|
REFERENCES |
|---|
|
Alkondon M and Albuquerque EX. Nicotinic acetylcholine receptor alpha7 and alpha4beta2 subtypes differentially control GABAergic input to CA1 neurons in rat hippocampus. J Neurophysiol 86: 3043–3055, 2001.
Alkondon M, Pereira EF, and Albuquerque EX. Alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res 810: 257–263, 1998.[CrossRef][Web of Science][Medline]
Alkondon M, Pereira EF, Barbosa CT, and Albuquerque EX. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther 283: 1396–1411, 1997.
Alkondon M, Pereira EF, Eisenberg HM, and Albuquerque EX. Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. J Neurosci 19: 2693–2705, 1999.
Alkondon M, Pereira EF, Eisenberg HM, and Albuquerque EX. Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks. J Neurosci 20: 66–75, 2000.
Alkondon M, Pereira EF, Wonnacott S, and Albuquerque EX. Blockade of nicotinic currents in hippocampal neurons defines methyllycaconitine as a potent and specific receptor antagonist. Mol Pharmacol 41: 802–808, 1992.[Abstract]
Alkondon M, Rocha ES, Maelicke A, and Albuquerque EX. Diversity of nicotinic acetylcholine receptors in rat brain. V. Alpha-Bungarotoxin-sensitive nicotinic receptors in olfactory bulb neurons and presynaptic modulation of glutamate release. J Pharmacol Exp Ther 278: 1460–1471, 1996.
Aram JA, Michelson HB, and Wong RK. Synchronized GABAergic IPSPs recorded in the neocortex after blockade of synaptic transmission mediated by excitatory amino acids. J Neurophysiol 65: 1034–1041, 1991.
Avoli M, Mattia D, Siniscalchi A, Perreault P, and Tomaiuolo F. Pharmacology and electrophysiology of a synchronous GABA-mediated potential in the human neocortex. Neuroscience 62: 655–666, 1994.[CrossRef][Web of Science][Medline]
Bandyopadhyay S, Gonzalez-Islas C, and Hablitz JJ. Dopamine enhances spatiotemporal spread of activity in rat prefrontal cortex. J Neurophysiol 93: 864–872, 2005.
Bandyopadhyay S, Sutor B, and Hablitz JJ. Cholinergic enhancement of synchronized interneuron activity in the rat neocortex. Soc Neurosci Abstr 950.15, 2004.
Bao W and Wu JY. Propagating wave and irregular dynamics: spatiotemporal patterns of cholinergic theta oscillations in neocortex in vitro. J Neurophysiol 90: 333–341, 2003.
Barkai E, Friedman A, Grossman Y, and Gutnick MJ. Laminar pattern of synaptic inhibition during convulsive activity induced by 4-aminopyridine in neocortical slices. J Neurophysiol 73: 1462–1467, 1995.
Beierlein M, Gibson JR, and Connors BW. A network of electrically coupled interneurons drives synchronized inhibition in neocortex. Nat Neurosci 3: 904–910, 2000.[CrossRef][Web of Science][Medline]
Benardo LS. Recruitment of GABAergic inhibition and synchronization of inhibitory interneurons in rat neocortex. J Neurophysiol 77: 3134–3144, 1997.
Bland BH. The physiology and pharmacology of hippocampal formation theta rhythms. Prog Neurobiol 26: 1–54, 1986.[CrossRef][Web of Science][Medline]
Blatow M, Rozov A, Katona I, Hormuzdi SG, Meyer AH, Whittington MA, Caputi A, and Monyer H. A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38: 805–817, 2003.[CrossRef][Web of Science][Medline]
Buzsaki G and Chrobak JJ. Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr Opin Neurobiol 5: 504–510, 1995.[CrossRef][Web of Science][Medline]
Calabresi P, Lacey MG, and North RA. Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording. Br J Pharmacol 98: 135–140, 1989.[Web of Science][Medline]
Chen K, Waller HJ, and Godfrey DA. Effects of endogenous acetylcholine on spontaneous activity in rat dorsal cochlear nucleus slices. Brain Res 783: 219–226, 1998.[CrossRef][Web of Science][Medline]
Christophe E, Roebuck A, Staiger JF, Lavery DJ, Charpak S, and Audinat E. Two types of nicotinic receptors mediate an excitation of neocortical layer I interneurons. J Neurophysiol 88: 1318–1327, 2002.
Chu Z, Galarreta M, and Hestrin S. Synaptic interactions of late-spiking neocortical neurons in layer 1. J Neurosci 23: 96–102, 2003.
Chu ZG, Zhou FM, and Hablitz JJ. Nicotinic acetylcholine receptor-mediated synaptic potentials in rat neocortex. Brain Res 887: 399–405, 2000.[CrossRef][Web of Science][Medline]
Cobb SR, Buhl EH, Halasy K, Paulsen O, and Somogyi P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378: 75–78, 1995.[CrossRef][Medline]
Cossart R, Bernard C, and 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]
DeFazio RA and Hablitz JJ. Horizontal spread of activity in neocortical inhibitory networks. Dev Brain Res 157: 83–92, 2005.[Medline]
DeFazio RA, Keros S, Quick MW, and Hablitz JJ. Potassium-coupled chloride cotransport controls intracellular chloride in rat neocortical pyramidal neurons. J Neurosci 20: 8069–8076, 2000.
Draguhn A, Traub RD, Schmitz D, and Jefferys JG. Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro. Nature 394: 189–192, 1998.[CrossRef][Medline]
Fisahn A, Pike FG, Buhl EH, and Paulsen O. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 394: 186–189, 1998.[CrossRef][Medline]
Frazier CJ, Buhler AV, Weiner JL, and Dunwiddie TV. Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18: 8228–8235, 1998.
Galarreta M and Hestrin S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402: 72–75, 1999.[CrossRef][Medline]
Gioanni Y, Rougeot C, Clarke PB, Lepouse C, Thierry AM, and Vidal C. Nicotinic receptors in the rat prefrontal cortex: increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission. Eur J Neurosci 11: 18–30, 1999.[CrossRef][Web of Science][Medline]
Gray R, Rajan AS, Radcliffe KA, Yakehiro M, and Dani JA. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383: 713–716, 1996.[CrossRef][Medline]
Grinvald A, Frostig RD, Lieke E, and Hildesheim R. Optical imaging of neuronal activity. Physiol Rev 68: 1285–366, 1988.
Huerta PT and Lisman JE. Heightened synaptic plasticity of hippocampal CA1 neurons during a cholinergically induced rhythmic state. Nature 19; 364: 723–725, 1993.
Jones S and Yakel JL. Functional nicotinic ACh receptors on interneurones in the rat hippocampus. J Physiol 504: 603–610, 1997.
Jones S, Sudweeks S, and Yakel JL. Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22: 555–561, 1999.[CrossRef][Web of Science][Medline]
Keros S and Hablitz JJ. Ectopic action potential generation in cortical interneurons during synchronized GABA responses. Neuroscience 131: 833–842, 2005.[Web of Science][Medline]
Lambe EK, Picciotto MR, and Aghajanian GK. Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28: 216–225, 2003.[CrossRef][Web of Science][Medline]
Larson J, Wong D, and Lynch G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 19; 368: 347–350, 1986.[CrossRef][Web of Science][Medline]
Lee MG, Hassani OK, Alonso A, and Jones BE. Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J Neurosci 25: 4365–4369, 2005.
Lena C and Changeux JP. Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders. Curr Opin Neurobiol 7: 674–682, 1997.[CrossRef][Web of Science][Medline]
Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol 53: 633–640, 2002.[CrossRef][Web of Science][Medline]
Le Novere N, Corringer PJ, and Changeux JP. The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53: 447–456, 2002.[CrossRef][Web of Science][Medline]
Louvel J, Papatheodoropoulos C, Siniscalchi A, Kurcewicz I, Pumain R, Devaux B, Turak B, Esposito V, Villemeure JG, and Avoli M. GABA-mediated synchronization in the human neocortex: elevations in extracellular potassium and presynaptic mechanisms. Neuroscience 105: 803–813, 2001.[CrossRef][Web of Science][Medline]
Lucas-Meunier E, Fossier P, Baux G, and Amar M. Cholinergic modulation of the cortical neuronal network. Pfluegers 446: 17–29, 2003.
Maelicke A, Coban T, Schrattenholz A, Schroder B, Reinhardt-Maelicke S, Storch A, Godovac-Zimmermann J, Methfessel C, Pereira EF, and Albuquerque EX. Physostigmine and neuromuscular transmission. Ann NY Acad Sci 681: 140–154, 1993.[Web of Science][Medline]
Maggi L, Sher E, and Cherubini E. Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus. J Physiol 536: 89–100, 2001.
McCormick DA and Prince DA. Mechanisms of action of acetylcholine in the guinea-pig cerebral cortex in vitro. J Physiol 375: 169–194, 1986.
McGehee DS, Heath MJ, Gelber S, Devay P, and Role LW. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269: 1692–1696, 1995.
Mechawar N, Cozzari C, and Descarries L. Cholinergic innervation in adult rat cerebral cortex: a quantitative immunocytochemical description. J Comp Neurol 428: 305–318, 2000.[CrossRef][Web of Science][Medline]
Mesulam MM, Mufson EJ, Wainer BH, and Levey AI. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10: 1185–1201, 1983.[CrossRef][Web of Science][Medline]
Michelson HB and Wong RK. Synchronization of inhibitory neurones in the guinea pig hippocampus in vitro. J Physiol 477: 35–45, 1994.
Newhouse PA, Potter A, and Levin ED. Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics. Drugs Aging 11: 206–228, 1997.[Web of Science][Medline]
Pereira EF, Alkondon M, Reinhardt S, Maelicke A, Peng X, Lindstrom J, Whiting P, and Albuquerque EX. Physostigmine and galanthamine: probes for a novel binding site on the alpha 4 beta 2 subtype of neuronal nicotinic acetylcholine receptors stably expressed in fibroblast cells. J Pharmacol Exp Ther 270: 768–778, 1994.
Picciotto MR, Caldarone BJ, King SL, and Zachariou V. Nicotinic receptors in the brain. Links between molecular biology and behavior. Neuropsychopharmacology 22: 451–465, 2000.[CrossRef][Web of Science][Medline]
Porter JT, Cauli B, Tsuzuki K, Lambolez B, Rossier J, and Audinat E. Selective excitation of subtypes of neocortical interneurons by nicotinic receptors. J Neurosci 19: 5228–5235, 1999.
Radcliffe KA and Dani JA. Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. J Neurosci 18: 7075–7083, 1998.
Raggenbass M and Bertrand D. Nicotinic receptors in circuit excitability and epilepsy. J Neurobiol 53: 580–589, 2002.[CrossRef][Web of Science][Medline]
Raghavachari S, Kahana MJ, Rizzuto DS, Caplan JB, Kirschen MP, Bourgeois B, Madsen JR, and Lisman JE. Gating of human theta oscillations by a working memory task. J Neurosci 21: 3175–3183, 2001.
Rao TS, Correa LD, Adams P, Santori EM, and Sacaan AI. Pharmacological characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists. Brain Res 990: 203–208, 2003.[CrossRef][Web of Science][Medline]
Roerig B, Nelson DA, and Katz LC. Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex. J Neurosci 17: 8353–8362, 1997.
Role LW and Berg DK. Nicotinic receptors in the development and modulation of CNS synapses. Neuron 16: 1077–1085, 1996.[CrossRef][Web of Science][Medline]
Sargent PB. The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci 16: 403–443, 1993.
Sarnthein J, Petsche H, Rappelsberger P, Shaw GL, and von Stein A. Synchronization between prefrontal and posterior association cortex during human working memory. Proc Natl Acad Sci USA 95: 7092–7096, 1998.
Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX, and Maelicke A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49: 1–6, 1996.[Abstract]
Sheridan RD and Sutor B. Presynaptic M1 muscarinic cholinoceptors mediate inhibition of excitatory synaptic transmission in the hippocampus in vitro. Neurosci Lett 108: 273–278, 1990.[CrossRef][Web of Science][Medline]
Sinha SR and Saggau P. Imaging of 4-AP-induced, GABA(A)-dependent spontaneous synchronized activity mediated by the hippocampal interneuron network. J Neurophysiol 86: 381–391, 2001.
Skinner FK, Zhang L, Velazquez JL, and Carlen PL. Bursting in inhibitory interneuronal networks: a role for gap-junctional coupling. J Neurophysiol 81: 1274–1283, 1999.
Steinlein OK, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic SF, Nakken KO, Propping P, and Bertrand D. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet 6: 943–947, 1997.
Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Scheffer IE, and Berkovic SF. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 11: 201–203, 1995.[CrossRef][Web of Science][Medline]
Storch A, Schrattenholz A, Cooper JC, Abdel Ghani EM, Gutbrod O, Weber KH, Reinhardt S, Lobron C, Hermsen B, Soskic V, Pereira EFR, Albuquerque EX, Methfessel C, and Maelicke A. Physostigmine, galanthamine and codeine act as ‘noncompetitive nicotinic receptor agonists’ on clonal rat pheochromocytoma cells. Eur J Pharmacol 290: 207–219, 1995.[CrossRef][Web of Science][Medline]
Tamas G, Somogyi P, and Buhl EH. Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat. J Neurosci 18: 4255–4270, 1998.
Vidal C and Changeux JP. Pharmacological profile of nicotinic acetylcholine receptors in the rat prefrontal cortex: an electrophysiological study in a slice preparation. Neuroscience 29: 261–270, 1989.[CrossRef][Web of Science][Medline]
Vidal C and Changeux JP. Nicotinic and muscarinic modulations of excitatory synaptic transmission in the rat prefrontal cortex in vitro. Neuroscience 56: 23–32, 1993.[CrossRef][Web of Science][Medline]
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, and Swanson LW. Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol 284: 314–335, 1989.[CrossRef][Web of Science][Medline]
Wang J, Wang X, Irnaten M, Venkatesan P, Evans C, Baxi S, and Mendelowitz D. Endogenous acetylcholine and nicotine activation enhances GABAergic and glycinergic inputs to cardiac vagal neurons. J Neurophysiol 89: 2473–2481, 2003.
Xiang Z, Huguenard JR, and Prince DA. Cholinergic switching within neocortical inhibitory networks. Science 281: 985–988, 1998.
Yang L and Benardo LS. Laminar properties of 4-aminopyridine-induced synchronous network activities in rat neocortex. Neuroscience 111: 303–313, 2002.[CrossRef][Web of Science][Medline]
Zhang L and Warren RA. Muscarinic and nicotinic presynaptic modulation of EPSCs in the nucleus accumbens during postnatal development. J Neurophysiol 88: 3315–3330, 2002.
Zhou FM and Hablitz JJ. Morphological properties of intracellularly labeled layer I neurons in rat neocortex. J Comp Neurol 376: 198–213, 1996.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  A. Klaassen, J. Glykys, J. Maguire, C. Labarca, I. Mody, and J. Boulter Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy PNAS, December 12, 2006; 103(50): 19152 - 19157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Soto, N. Kopell, and K. Sen Network Architecture, Receptive Fields, and Neuromodulation: Computational and Functional Implications of Cholinergic Modulation in Primary Auditory Cortex J Neurophysiol, December 1, 2006; 96(6): 2972 - 2983. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
