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1Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina; and 2Department of Physiology, Northwestern University Medical School, Chicago, Illinois
Submitted 8 August 2006; accepted in final form 12 March 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). ACh levels in the medial prefrontal cortex (PFC) rise during performance of tasks that demand attention (Passetti et al. 2000), and intra-PFC injections of the muscarinic receptor antagonist scopolamine disrupts task performance (Robbins et al. 1998). Recordings from PFC neurons during performance of a sustained visual-attention task revealed that cholinergic deafferentation of this region significantly reduced both baseline firing as well as task-related activity (Gill et al. 2000). In particular, cholinergic deafferentation significantly blunted the enhanced activity of PFC neurons seen in response to the addition of distractors.
It has long been known that stimulation of muscarinic receptors depolarizes cortical pyramidal neurons (Krnjevic 2004). Although some investigators have suggested that the depolarization is mediated by the activation of a nonselective cation current (Fisahn et al. 2002; Haj-Dahmane and Andrade 1996; Klink and Alonso 1997), earlier reports attributed the effect to the closure of a standing potassium (K+) conductance (Benson et al. 1988; Madison et al. 1987). Pyramidal neurons express a broad array of K+ channels but most are not open at the resting membrane potential. One channel that is open, making it a potential candidate, is formed by Kir2 subunits (Stanfield et al. 2002). These inwardly rectifying channels help set the resting membrane potential of PFC pyramidal neurons as well as the integration of excitatory synaptic inputs (Day et al. 2005). The open probability of Kir2 channels is modulated by an interaction with the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2) (Stanfield et al. 2002). Depletion of membrane PIP2 by activation of membrane phospholipases, such as phospholipase C (PLC), lowers the open probability of Kir2 channels. Because the effects of ACh on pyramidal neurons are largely mediated by M1 muscarinic receptors that stimulate PLC (Benson et al. 1988), it is plausible that closure of Kir2 K+ channels is responsible, at least in part, for the membrane depolarization. The experiments described here were aimed at testing this hypothesis. Our results show that indeed Kir2 K+ channel currents are reduced by M1 receptor stimulation in layer V pyramidal cells of the rodent prelimbic/infralimbic (PL/IL) cortex, resulting in a membrane depolarization. As expected, closure of these channels appears to be dependent on depletion of PIP2 from the membrane. In addition to membrane depolarization, closure of the largely dendritic Kir2 channels dramatically enhances the summation of excitatory synaptic potentials.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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) were cut on a vibrating tissue slicer (Leica) and transferred to a holding chamber where they were incubated in ACSF at 35°C for 30 min. Slices were subsequently stored at room temperature until recording. All ACSF solutions were constantly bubbled with 95% O2-5% CO2 to maintain pH 
7.4.
Whole cell current and voltage-clamp recordings were performed using standard techniques. Slices were transferred to a submersion type recording chamber and were constantly perfused (
2 ml/min) with warmed (32 ± 1°C) ACSF. Layer V pyramidal neurons were visualized using either an Olympus BX51 or Zeiss Axioskop 2FS microscope equipped with IR-DIC optics and a Dage-MTI infrared video camera. Glass micropipettes were filled with an internal solution containing (in mM) 130 KMeSO4, 5 KCl, 2 MgATP, 0.5 Na2GTP, 5 HEPES, 0.5 CaCl2, 5 EGTA, and 0.1 spermine, pH 7.3, 270 mosM/l. Spermine was included in the internal solution to maintain the inwardly rectifying character of Kir2 channels (Ficker et al. 1994). The pipette resistance, as measured in the bath, was typically 3.5–4.5 M
. Current- and voltage-clamp recordings were obtained using a Multiclamp 700A or 700B amplifier, a Digidata 1322 A/D converter and pClamp software (Axon Instruments). Records were not corrected for the liquid junction potential, which was estimated to be 6–7 mV. As a consequence, the actual membrane potentials should have be 6–7 mV more negative than those reported here.
Data were analyzed using Clampfit (Axon Intruments) and IgorPro (Wavemetrics) software. Statistical analyses were performed using SPSS (Chicago, IL). In data presented as box plots, the central line represents the median, the edges of the box represents the intraquatrile range, and the "whisker lines" show the extent of the overall distribution, excluding points 1.5 times the intraquatrile range that are considered outliers and are shown as circles.
All reagents were obtained from Sigma (St. Louis, MO) with the exception of KMeSO4 (ICN Biochemicals), NaGTP (Roche), TTX (Alomone Labs), CNQX, APV and ZD7288 (Tocris), thapsigargin, and chelrythrine chloride (Calbiochem). All cholinergics, channel blockers and signal transduction reagents were prepared as concentrated stock solutions in distilled water and either added immediately to ACSF at working concentrations or frozen at –20°C until use.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Bath application of the muscarinic cholinergic agonist carbachol (CCh, 10 µM) depolarized pyramidal neurons, leading to repetitive spiking (Fig. 1A). The CCh effect was antagonized by atropine (1 µM, n = 3, data not shown) or the M1 receptor antagonist pirenzepine (2 µM, n = 4, Fig. 1B) but not by the M2/M4 antagonist gallamine (2 µM, n = 4, Fig. 1C). Blockade of AMPA and N-methyl-D-aspartate (NMDA) receptors with kynurenic acid (1.5 mM) or a combination of CNQX (10 µM) and APV (50 µM) did not prevent the CCh induced depolarization and spiking (data not shown), demonstrating that the effect was not synaptically mediated.
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M1 receptor stimulation reduces inwardly rectifying potassium currents
We have previously shown that blockade of constitutively active inwardly rectifying potassium (Kir2) channels depolarizes PL/IL pyramidal neurons, leading to tonic firing (Day et al. 2005). Given the similarity of the responses to Kir2 channel blockade and M1 receptor stimulation in these cells, we sought to determine whether M1 receptors inhibit Kir2 channels. In the presence of TTX (500 nM) and the HCN channel blocker ZD 7288 (40–50 µM), somatic hyperpolarizing voltage steps from –60 mV evoke a Ba2+-sensitive current which is largely carried by Kir2 channels (Fig. 2A) (Day et al. 2005). CCh (10 µM) reduced these currents, particularly at membrane potentials below the K+ equilibrium potential. Subtracting currents evoked in the presence of CCh from those evoked in its absence, yielded estimates of the CCh-sensitive current (Fig. 2B). The current-voltage plot of this current was very similar to that of the Ba2+-sensitive current (Fig. 2C). Both currents reversed close to the predicted K+ reversal potential (EK) and showed prominent rectification above EK (Fig. 2C). Similar results were obtained using voltage ramps from –120 to –50 mV (100 ms, Fig. 2D). Scaling the CCh-sensitive current revealed that it rectified more strongly than the Ba2+-sensitive current (Fig. 2E), consistent with the notion that CCh preferentially targeted strongly rectifying Kir2 channels. In spite of the rectification, these channels do pass outward current above EK and reducing their open probability will result in a net inward, depolarizing current.
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). If these channels were tonically activated by a Gi/o-coupled receptor, membrane depletion of PIP2 by M1 receptors could reduce their open probability (Stanfield et al. 2002). To test this hypothesis, the Kir3 channel blocker tertiapin was used. When applied alone, tertiapin (30 nM) produced little or no change in holding current (Fig. 3G), suggesting that Kir3 channels were not tonically active in our slices. Moreover, tertiapin had no effect on the magnitude of the CCh-sensitive currents (Fig. 3, F and G; n = 5), suggesting that modulation of Kir3 channels was not a significant factor in our experiments. M1 receptors reduce Kir2 channel currents by depleting membrane PIP2
M1 muscarinic receptors are positively coupled to phospholipase C (PLC) by G
q proteins (Richardson 1995). To determine if activation of PLC is required for the CCh-induced inhibition of Kir2 currents, neurons were dialyzed with the PLC inhibitor U-73122 (20 µM). U-73122 (0.2 µM) was also added to the bath. Under these conditions, the inward current produced by CCh was almost completely blocked (Fig. 4, A and D, n = 4; P < 0.05, Mann-Whitney) indicating that the M1 receptor-mediated inhibition of Kir2 currents requires activation of PLC.
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; Zhu et al. 1999) and in nucleus basalis neurons (Takano et al. 1995). To determine if PKC was important in PL/IL pyramidal neurons, CCh was applied after a 5- to 10-min incubation in the PKC inhibitor chelerythrine chloride (1 µM). This had no effect on the modulation (Fig. 4, B and D, n = 6), suggesting that the M1 receptor mediated inhibition of Kir2 channels does not depend on PKC. In addition to stimulating PKC, activation of PLC also results in the increased production of IP3, which releases Ca2+ from intracellular stores. To test whether the M1 receptor mediated inhibition of Kir2 currents depended on this linkage, CCh was applied after inhibiting Ca2+-ATPase with thapsigargin (5 µM), which is known to deplete intracellular Ca2+ stores. Thapsigargin had no effect on the response to CCh (Fig. 4, C and D), suggesting that the M1 receptor modulation of Kir2 channels was not dependent on the release of intracellular Ca2+.
Recent studies have shown that Kir2 channel opening is strongly dependent on PIP2 binding (Stanfield et al. 2002). Depletion of membrane PIP2, decreases channel open probability, as does M1 receptor stimulation. Because M1 receptors activate PLC, which results in the hydrolysis and depletion of PIP2, this parallel is not surprising. If this is the mechanism by which M1 receptors close Kir2 channels, then blocking the resynthesis of PIP2 should prevent reversal of the modulation. Indeed, inhibiting phosphoinositide-3-kinase (PI3K) with wortmannin (40 µM) significantly blunted the reversal of the CCh modulation (Fig. 4, E and F, n = 9; P < 0.01, Mann-Whitney).
M1 receptor stimulation enhances temporal integration of EPSPs evoked by layer I stimulation
We have previously shown that blockade of Kir2 channels markedly enhances temporal integration of EPSPs (Day et al. 2005). To determine if M1 receptor stimulation also enhanced temporal summation of EPSPs, we recorded from layer V pyramidal neurons and evoked synaptic potentials with a stimulating electrode placed in layer I. The somatic membrane potential was held near –70 mV to reduce the voltage-dependent effects on measurements of summation. In the absence of CCh, EPSPs evoked by a 40-Hz stimulus train summed sublinearly; the ratio of the amplitude of the fifth to the first EPSP in the train (EPSP5/EPSP1) was typically between 1 and 2 (Fig. 5, A and C). In the presence of CCh (10 µM), the EPSP5/EPSP1 ratio significantly increased to a median value of 4.3 (Fig. 5, A and C; n = 5, P < 0.05, Wilcoxon signed-ranks test). In addition, CCh significantly reduced the amplitude of the first EPSP in the train (Fig. 5, A and B, inset; n = 5, P < 0.05, Wilcoxon signed-ranks test). This observation is consistent with previous reports of M2/4 muscarinic receptors located on glutamatergic terminals (Mrzljak et al. 1993) which act to reduce evoked glutamate release (Kimura and Baughman 1997; Levy et al. 2006). To determine if the CCh-induced enhancement of summation was due to an action on these presynaptic receptors (Brenowitz and Trussell 2001), the experiments were repeated in the presence of the M2/M4 antagonist, gallamine (2 µM). In this situation, the amplitude of the first EPSP in the train was not reduced by CCh (Fig. 5B, inset, n = 7). However, the EPSP5/EPSP1 ratio was still significantly enhanced (Fig. 5, B and C, n = 7, P < 0.05, Wilcoxon signed-ranks test).
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), Ba2+ significantly enhanced the EPSP5/EPSP1 ratio (Fig. 5D, n = 5, P < 0.05, Wilcoxon signed-ranks test); in the presence of Ba2+, CCh failed to further increase the EPSP5/EPSP1 ratio (Fig. 5D), suggesting that down-regulation of Kir2 channels was the principal means of achieving the change in EPSP summation. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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M1 receptors target Kir2 channels in PL/IL pyramidal cells
In agreement with previous anatomical and physiological studies (Krnjevic 2004), the effects of CCh on pyramidal neuron excitability were mediated by largely by pirenzipine-sensitive M1 muscarinic receptors. The experiments presented here suggest that activation of these receptors led to a reduction in inwardly rectifying K+ currents that were attributable to flux through Kir2 channels that are known to be robustly expressed by these neurons (Day et al. 2005). The involvement of Kir2 channels is supported by four observations. First, the CCh-sensitive current was inwardly rectifying, having a current-voltage profile strongly resembling that of Kir2 channels in other preparations (Stanfield et al. 2002). Second, channels targeted for modulation were K+ selective as flux through them reversed near EK. Third, the CCh-sensitive current was blocked by Cs+ or Ba2+, both of which block Kir2 channels in the concentration range used. Last, the M1 receptor modulation was not altered by disruption of PKC or intracellular Ca2+ signaling (Haj-Dahmane and Andrade 1998) but rather PIP2 metabolism. Binding of PIP2 to the C-terminus of Kir2 channel subunits is necessary for channel opening (Stanfield et al. 2002). Our observations are consistent with a growing literature showing M1 muscarinic receptor stimulation of PLC leads to depletion of membrane PIP2 and closure of Kir2 channels (Chuang et al. 1997; Du et al. 2004). Interestingly, the sensitivity of Kir2 channels to depletion of PIP2 and modulation by G-protein-coupled receptor (GPCR) signaling cascades through PLC is dependent on the subunit composition of the channels. There are four Kir2 subunits that have been cloned (Kir2.1–4). Channels composed of Kir2.3 subunits, which are prominently expressed in PL/IL pyramidial neurons (Day et al. 2005), are very sensitive to alterations in membrane PIP2 content, and activation of PLC linked GPCRs, like the M1 muscarinic receptor (Du et al. 2004).
M1 receptors modulation of Kir2 K+ channels is likely to be part of a coordinated response
Our results are consistent with previous observations from neurons in the hippocampus, cortex, and striatum showing that muscarinic receptor stimulation reduces opening of K+ channels with properties resembling those of Kir2 channels (Hsu et al. 1996; Krnjevic 2004; Uchimura and North 1990). However, others have attributed the depolarizing actions of muscarinic receptor stimulation in pyramidal neurons to the opening of a mixed cation channel (Fisahn et al. 2002; Haj-Dahmane and Andrade 1996; Klink and Alonso 1997). Although we did not observe any evidence of a CCh-activated cation channel in our experiments, we cannot exclude their participation in the M1 receptor response in other circumstances; it is also possible that some mechanisms might have been attenuated by whole cell recording (e.g., modulation of Kv7/KCNQ channels) (Shen et al. 2005). Moreover, in vivo, it is likely that ACh alters other aspects of network activity, potentially engaging other neuromodulatory mechanisms.
ACh, Kir2 channels, and cortical state transitions
In vivo intracellular recordings of cortical pyramidal neurons in either anesthetized or sleeping animals exhibit large-amplitude, rhythmic fluctuations in membrane potential characterized by periods of depolarization (approximately –55 mV) and irregular spike firing interspersed with large-amplitude (10–20 mV), long-lasting (500 ms) hyperpolarizations. (Metherate et al. 1992; Steriade et al. 2001). The transition from sleep to active waking is accompanied by the loss of these long-lasting, large amplitude hyperpolarizing periods (Steriade et al. 2001). The standing outward current generated by Kir2 channels should help to stabilize these hyperpolarized epochs. There are several pieces of evidence that suggest the shift to tonic depolarization during wakefulness is due to Ach-mediated suppression of these channels. As animals transition from sleep to active waking, cortical ACh levels increase (Marrosu et al. 1995) and in parallel the input resistance of cortical neurons increases (Steriade et al. 2001), consistent with a closure of Kir2 channels during wakefulness. In anesthetized animals, stimulation of the nucleus basalis (NB), the principal source of cortical ACh, blocks these large amplitude hyperpolarizing periods, shifting the neurons into a tonically depolarized state (Metherate et al. 1992). This effect of NB stimulation is prevented by iontophoresis of atropine (Metherate et al. 1992) and mimicked by intracellular perfusion with the Kir2 channel blocker cesium (Metherate and Ashe 1993).
Cholinergic modulation of Kir2 channels enhances temporal summation of EPSPs
Previous work has shown that Kir2.2 and Kir2.3 channels are expressed in the dendrites of PFC pyramidal neurons where they influence the temporal integration of distally generated EPSPs (Day et al. 2005). Here, where cells were manually "clamped" near their resting membrane potential, M1-mediated inhibition of Kir2 channels produced a significant enhancement in the temporal summation of evoked EPSPs. This enhancement is largely attributable to the elevation in dendritic input impedance after Kir2 channel closure (Day et al. 2005). In the absence of a somatic voltage clamp, inhibition of Kir2 channels also will depolarize the dendritic membrane and deactivate HCN channels (Day et al. 2005). The deactivation of HCN channels should work in concert with the closure of Kir2 channels to enhance the temporal summation of EPSPs (Day et al. 2005; Magee 2000).
The cortical effects of ACh are not limited to modulation of postsynaptic Kir2 channels in pyramidal neurons. CCh also significantly reduced the amplitude of the first EPSP in the stimulus train. As closure of Kir2 channels should increase the amplitude of the first EPSP, this modulation is likely due to a presynaptic action. Previous work has shown that presynaptically located M2/4 muscarinic receptors (Mrzljak et al. 1993) reduce glutamate release at intracortical terminals (Kimura and Baughman 1997; Levy et al. 2006). In agreement with these observations, the M2/4 antagonist gallamine blocked the CCh-induced suppression of the initial EPSP, arguing that this component of the response was presynaptically mediated. This distribution of effects differs from that found in hippocampal CA1 pyramidal neurons where postsynaptic M2/4 muscarinic receptors activate Kir3 channels, reducing the amplitude of the response to exogenous glutamate application (Seeger and Alzheimer 2001). The absence of a CCh-evoked current in the presence of the M1 antagonist, pirenzepine (Fig. 1D, inset), argues against the presence of similar mechanisms in PF/IF layer V pyramidal neurons. In fact, the presynaptic- and postsynaptic effects of ACh in PF/IF pyramidal neurons complement one another. By reducing release probability, presynaptic inhibition increases the fidelity of the synaptic response to repetitive stimulation (Brenowitz and Trussell 2001). As shown here, the postsynaptic reduction in Kir2 channel currents enhances the temporal summation EPSPs. The combination of these effects led to larger enhancement in the EPSP5/EPSP1 ratio than seen with just the postsynaptic M1 receptor modulation alone (Fig. 5C). Thus ACh reduced the postsynaptic consequences of a single, isolated presynaptic event but enhanced the response to a temporally coherent burst of synaptic activity. These findings suggest that elevations in PFC ACh levels during the performance of working-memory tasks, serve to enhance the response to salient, sustained stimuli while suppressing the response to weaker, transient distracting events.
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FOOTNOTES |
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Address for reprint requests and other correspondence:D. J. Surmeier, Dept. of Physiology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611 (E-mail: j-surmeier{at}northwestern.edu)
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REFERENCES |
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