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. 2006 Aug 24;576(Pt 3):865–872. doi: 10.1113/jphysiol.2006.118232

Functional somato-dendritic α7-containing nicotinic acetylcholine receptors in the rat basolateral amygdala complex

Rebecca C Klein 1, Jerrel L Yakel 1
PMCID: PMC1890412  PMID: 16931547

Abstract

Multiple subtypes of nicotinic acetylcholine receptors (nAChRs) are expressed in the CNS. The amygdala complex, the limbic structure important for emotional memory formation, receives cholinergic innervation from the basal forebrain. Although cholinergic drugs have been shown to regulate passive avoidance performance via the amygdala, the neuronal subtypes and circuits involved in this regulation are unknown. In the present study, whole-cell patch-clamp electrophysiological techniques were used to identify and characterize the presence of functional somato-dendritic nAChRs within the basolateral complex of the amygdala. Pressure-application of acetylcholine (ACh; 2 mm) evoked inward current responses in a subset of neurons from both the lateral (49%) and basolateral nuclei (72%). All responses displayed rapid activation kinetics, and were blocked by the α7-selective antagonist methyllycaconitine. In addition, the α7-selective agonist choline induced inward current responses that were similar to ACh-evoked responses. Spiking patterns were consistent with pyramidal class I neurons (the major neuronal type in the basolateral complex); however, there was no correlation between firing frequency and the response to ACh. The local photolysis of caged carbachol demonstrated that the functional expression of nAChRs is located both on the soma and dendrites. This is the first report demonstrating the presence of functional nAChR-mediated current responses from rat amygdala slices, where they may be playing a significant role in fear and aversively motivated memory.

Nicotinic acetylcholine receptors (nAChRs) are in the superfamily of Cys-loop ligand-gated ion channels that also includes the serotonin 5-HT3, GABA and glycine receptor channels. Neuronal nAChRs are involved in a variety of physiological processes such as mediating fast synaptic signalling, regulating neurotransmitter release and maintaining cognitive performance (Jones et al. 1999). In addition, dysfunctions in nAChRs may be a factor in a variety of neurodegenerative diseases (including Alzheimer's disease and Parkinson's disease), neurological disorders (including epilepsy and schizophrenia), and in ageing (Nordberg, 1994; Steinlein et al. 1995; Freedman et al. 1997; Jones et al. 1999; Paterson & Nordberg, 2000; Court et al. 2001; Dani, 2001).

Neuronal nAChRs are known to be widely expressed throughout the central nervous system (CNS), and postsynaptic or somato-dendritic nAChRs have been extensively characterized, particularly in the hippocampus and cortex (Jones & Yakel, 1997; Roerig et al. 1997; Alkondon et al. 1998; Frazier et al. 1998; Jones et al. 1999; McQuiston & Madison, 1999; Porter et al. 1999). However, increasing evidence for cholinergic influence via nAChRs in other neurotransmitter pathways has prompted more detailed characterization in other brain regions such as the supraoptic nucleus (Hatton & Yang, 2002), substantia nigra (Matsubayashi et al. 2004), the medial septal diagonal band complex (MS/DB; Thinschmidt et al. 2005), and the nucleus hypoglossus (Quitadamo et al. 2005).

Another important brain region highly regulated by cholinergic input is the amygdala, an almond-shaped structure in the temporal lobe consisting of more than 10 distinct nuclei located in the limbic system (Sah et al. 2003). This complex coordinates the autonomic and endocrine responses of emotional states, and plays a role in passive avoidance performance. In addition to the primary glutamatergic projections from the cerebral cortex, the amygdala receives a cholinergic projection from the basal forebrain via the nucleus basalis magnocellularis (Sah et al. 2003). Reciprocal connections between the amygdala and hippocampus, in particular projections from the ventral CA1 and subiculum, appear to primarily target the basolateral (BLA) nucleus (Canteras & Swanson, 1992; Sah et al. 2003; Phelps & LeDoux, 2005), and have been reported to influence aversive learning and memory (McGaugh et al. 1990).

It is well established that the nAChR system plays a significant role in hippocampal-dependent working memory tasks, where systemic or local infusion of nicotinic receptor agonists increases performance, while antagonists result in working memory deficits (Levin, 2002). Multiple behavioural protocols studied in rats have demonstrated a similar effect for nAChR signalling in the amygdala. For example, nicotine can regulate passive avoidance performance when infused bilaterally into the BLA nucleus (Blozovski & Dumery, 1987). More recently, the acute infusion of methyllycaconitine (MLA; to inhibit α7 nAChRs) and dihydro-β-erythroidine (DHβE; to inhibit non-α7 nAChRs) into the BLA nucleus caused significant working memory impairments in the radial-arm maze (Addy et al. 2003). Similarly, the infusion of nicotine into the BLA nucleus significantly enhanced short- and long-term memory formation, while the nAChR antagonist mecamylamine inhibited this process (Barros et al. 2005).

Despite accumulating evidence for nAChR involvement in amygdala-mediated working memory tasks, little is known regarding the location and mechanistic role of nAChRs in this brain region. Thus far, only reports describing a presynaptic role for nAChRs have appeared. For example, for the olfactory projections to the amygdala, the activation of presynaptic nAChRs can modulate glutamatergic as well as GABAergic synaptic transmission (Barazangi & Role, 2001). Additionally in recordings from the BLA nucleus, the local application of ACh increased spontaneous GABAergic IPSCs by activating (via α3β4-containing nAChRs) GABAergic neurons (Zhu et al. 2005).

In the current study, whole-cell patch-clamp electrophysiological techniques were used to identify and characterize the presence of functional nAChRs in the basolateral amygdala complex in acutely isolated rat brain slices. The pressure application of acetylcholine, as well as the laser-induced photolysis of caged carbachol, revealed that functional somato-dendritic nAChRs are present in a subset of neurons within the lateral (LA) and BLA nuclei. This is the first report demonstrating that rat amygdala neurons express functional somato-dendritc nAChR-mediated current responses, where they are likely to be playing an important role in emotionally motivated aspects of nicotine addiction and working memory performance.

Methods

Slice preparation

All experiments were carried out in accordance with guidelines approved by the NIEHS Animal Care and Use Committee, which includes minimizing the number of animals used and their suffering. Standard techniques were used to prepare acute amygdala slices (350 μm thick) from 14- to 21-day-old-rats (Klein & Yakel, 2004). Briefly, rats were anaesthetized with halothane and decapitated. Brains were quickly removed and placed in ice-cold oxygenated artificial cerebral spinal fluid (ACSF) containing (mm): 119 NaCl, 2.5 KCl, 1.3 MgCl2, 2.5 CaCl2, 1 NaH2PO4, 26.2 NaHCO3 and 11 glucose. Upon dissection, brain chunks were glued to the stage of a vibratome (VT1000S; Leica, Germany) and immersed in the cooled oxygenated ACSF. Slices were then used for recordings within 6 h, and after at least 1 h of recovery period.

Electrophysiology

Whole-cell patch-clamp recordings were performed using patch pipettes (Garner 7052 or 8250 glass, with resistances of 3–4 MΩ) filled with a solution containing (mm): 140 potassium gluconate, 0.5 CaCl2, 2 MgATP, 2 MgCl2, 5 EGTA, 0.2 Oregon Green and 10 Hepes (pH 7.2–7.3). For constructing the current–voltage relationship, the following solution was used (mm): 130 caesium gluconate, 2 NaCl, 4 Na2ATP, 0.4 Na2GTP, 4 MgCl2 and 20 Hepes (pH 7.2–7.3). Slices were superfused at room temperature (18–22°C) with ACSF. Cells were clamped at −70 mV (unless otherwise indicated), and holding potential values were corrected for a junction potential of 10 mV. Responses were induced by pressure application (5–100 ms duration pulses at 10 p.s.i. (69 kPa) pressure) of either ACh (2 mm) or choline (10 mm) via a glass pipette placed 5–10 μm from the cell body using a Picospritzer II (General Valve Co., Fairfield, NJ, USA). Current signals were recorded using an Axopatch 200B amplifier, filtered at 1 kHz, and sampled at 10 kHz using pClamp 8.2 software (Axon Instruments). Statistical analyses were performed using Origin software (Microcal, Northampton, MA, USA) and averaged data were presented as means ± s.e.m. Statistical significance (P < 0.05) was assessed using a Student's t test. Firing properties and electrical excitability were assessed using whole-cell current-clamp mode. Hyper- and depolarizing step pulses were delivered at 1 s durations ranging from −0.3 to 0.3 nA in 50 pA increments.

Local photolysis

Neurons were visualized using a fast-scanning confocal microscope (Radiance 2100; Bio-Rad, UK). Oregon Green-BAPTA (0.2 mm; Molecular Probes) was dialysed into the cell via the patch pipette, and its fluorescence was excited with 488 nm light and recorded using a 515 ± 15 nm bandpass filter. For local photolysis of caged carbachol, the 351–364 nm output of a continuous emission argon ion laser (Spectra Physics Stabilite 2017) was delivered via a multimode optical fibre (OZ Optics, Ontario, Canada) and a precision UV spot positioning device (Prairie Technologies, Middleton, WI, USA), through an Olympus ×40 water-immersion objective (Khiroug et al. 2003). CNB-caged carbachol (Molecular Probes) was added to the ACSF and delivered to the vicinity of the patch-clamped cell using an UltraMicroPump II syringe pump (WPI, Sarasota, FL, USA) at the flow rate of 10 μl min−1. Quartz syringe tips (250 μm i.d.) were placed just above the slice surface to ensure homogenous coverage of the cell. The use of the syringe pump allowed reliable application of maximal concentrations of caged carbachol during continuous superfusion of the slice with fresh oxygenated ACSF.

Unless otherwise indicated, all chemicals were purchased from Sigma.

Results

Functional nAChRs in the basolateral amygdala complex

Whole-cell patch-clamp recordings were performed on neurons in acute slices within the LA and BLA nuclei of the amygdala. The focal pressure application of acetylcholine (ACh; 2 mm; 15 ms duration pulses) elicited rapidly activating and decaying inward current responses in both LA and BLA neurons (Fig. 1, left traces), indicating that these neurons expressed functional nAChRs. BLA neurons were more responsive as 72% (n = 32 cells) of these neurons had functional ACh-induced responses, whereas only 49% (n = 53) of the LA neurons did. However, peak current amplitudes did not differ significantly between the two regions where the average amplitudes were −128 ± 14 and −140 ± 22 pA in BLA and LA neurons, respectively. The rise time (10–90%) and half-time of decay were also similar in both nuclei; these values were, respectively, 8.2 ± 1 and 16 ± 3 ms (n = 23) for BLA neurons, and 10 ± 1 and 16 ± 1 ms (n = 24) for LA neurons.

Figure 1. Neurons in the basolateral amygdala complex express functional postsynaptic nicotinic acetylcholine receptors (nAChRs).

Figure 1

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Left, representative traces of inward currents evoked by somatic pressure application of ACh (2 mm) in a neuron from the basolateral (BLA) nucleus (A) and lateral (LA) nucleus (B). Scale bar, 50 pA, 100 ms. Right, corresponding spiking patterns for each responsive neuron at threshold and above threshold are shown, as well as the response to hyperpolarizing current injection. Scale bar, 25 mV, 250 ms. C, depolarization and single action potential spike induced by 15 ms pulse of ACh (2 mm) under current-clamp mode. Scale bar, 50 ms. D, current–voltage (I–V) relationship of ACh responses in BLA neurons. Responses induced at various holding potentials were normalized to the response at −70 mV (n = 4–8 for each holding potential).

Depolarizing current injections under current-clamp mode were given to assess the firing pattern in both ACh-responsive and non-responsive neurons. Above-threshold current injections in non-responsive neurons from the LA nucleus displayed firing frequencies ranging from 13 to 31 Hz with an average of 20 ± 1 Hz (9 ± 2 Hz at threshold; n = 9), while responsive neurons had firing frequencies ranging from 10 to 24 Hz with an average of 17 ± 1 Hz (6 ± 1 Hz at threshold; n = 12) (Fig. 1B, right traces). In the BLA nucleus, non-responsive neurons displayed firing frequencies ranging from 17 to 31 Hz with an average of 24 ± 2 Hz (8 ± 1 Hz at threshold; n = 18), while responsive neurons had firing frequencies ranging from 10 to 24 with an average of 22 ± 1 Hz (8 ± 1 Hz at threshold; n = 14) (Fig. 1A, right trace). The majority of the neurons studied in both the LA and BLA nuclei had regular-spiking action potential firing properties. Although there was variability in spiking patterns among the neurons examined, there was no obvious correlation between firing properties and ACh responsiveness.

Under current-clamp mode, the pressure application of ACh (2 mm; 15 ms) induced firing of a single action potential in 20% (n = 20) of BLA neurons (Fig. 1C), and depolarized neurons by 10 ± 2 mV (n = 4). In the cells where no firing was induced, ACh depolarized neurons by 5.8 ± 0.8 mV (n = 16). There was a correlation between the amplitude of the ACh-induced current response (under voltage clamp) and the presence of action potential generation, where the average current amplitude in firing cells was −230 ± 30 pA (n = 4) versus −150 ± 20 pA (n = 16) in non-excited cells. The current–voltage (i.e. I–V) relationship for ACh-induced current responses is shown in Fig. 1D, and demonstrates a relatively linear relationship for negative voltage ranges, a potential with zero net current flow of approximately +10 mV, and inward rectification typical of that seen for nAChR-mediated responses in hippocampal interneurons (Jones & Yakel, 1997; Shao & Yakel, 2000).

Functional nAChRs in BLA complex are predominantly α7-containing

Based on the rapid kinetic profile of the nAChR-mediated responses from both the LA and BLA neurons, several approaches were used to further characterize the nature of the ACh responses. First, we tested whether the α7-specific antagonist MLA was able to block the ACh (2 mm)-induced responses. As illustrated in Fig. 2A and B, peak currents in both the LA (n = 6) and BLA (n = 4) neurons were completely blocked by the bath application of MLA (5–10 nm). Recovery from MLA block was incomplete and slow (>20 min), as observed by others in slices (Klink et al. 2001). Secondly, pressure application of the α7 nAChR-selective agonist choline (10 mm; 15 ms duration pulses) (Papke et al. 1996) induced inward current responses in 62% of BLA neurons (n = 13; Fig. 2C) that were similar in amplitude and kinetics to ACh-evoked responses. The average amplitude, rise-time, and half-time of decay for choline-induced responses were −143 ± 49 pA, 6.8 ± 0.5 ms, and 16 ± 4 ms, respectively; these values were not significantly different from ACh-induced responses. Finally, ACh-evoked current responses were unaffected by the bath application of the glutamate receptor antagonist CNQX (20 μm; n = 4) (data not shown). Taken together, these data indicate that ACh-responsive neurons in both nuclei express functional α7-containing nAChRs (Klink et al. 2001), and neither glutamate release nor glutamate receptor activation was involved in these responses.

Figure 2. Functional nAChRs in the amygdala are methyllycaconitine sensitive, and activated by choline.

Figure 2

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A, representative traces of 2 mm ACh-evoked currents in an LA neuron before and during application of methyllycaconitine (MLA; 10 nm). Scale, 25 pA, 500 ms. B, plot of current amplitude (percentage of control) versus time upon bath application (bar) of MLA compared with baseline from the LA neuron (•) shown in A (representative of 5 neurons), and a BLA neuron (○) (representative of 4 neurons). C, representative trace illustrating inward current evoked by pressure application of the choline (10 mm) in a BLA neuron (left; scale bar, 50 pA, 100 ms) and corresponding spiking pattern (right) at threshold, above threshold, as well as the response to hyperpolarizing current injection (scale bar, 25 mV, 250 ms).

Kinetics of desensitization and recovery of α7-containing nAChRs in BLA neurons

The desensitization properties of the α7-containing nAChRs on BLA neurons were assessed by applying dual pressure pulses of ACh (2 mm; 15 ms duration) at varying intervals between 1 and 30 s (Fig. 3). To quantify the rate of recovery from desensitization (Fig. 3B), we compared the relative amplitude of the second response to the amplitude of the first. Under these conditions, the maximal desensitization was observed at the 1 s interval, while responses fully recovered within 30 s. An exponential fit of the amplitude ratio versus the time interval between these two pulses (Fig. 3B) yielded a rate of recovery from desensitization of 6.4 ± 1 s (n = 9–11 neurons for each time point).

Figure 3. Desensitization and recovery of ACh-evoked responses in BLA neurons.

Figure 3

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A, representative traces of a BLA neuron illustrating the desensitization of ACh (2 mm) evoked current when two applications (15 ms) were given at a 3 s interval. Scale, 50 pA, 1 s. B, plot of the ratio of the response evoked by the second application (Resp2) relative to the response evoked by the first application (Resp1) versus the time interval between applications. An exponential fit of the plotted data produced a time constant of 6.4 ± 1 s for the recovery from desensitization (n = 9–11 for each data point). C, representative trace illustrating the onset of desensitization during a 100 ms (bar) application of ACh (2 mm) (n = 6). Scale bar, 25 pA, 100 ms.

To determine the rate of onset of desensitization in the continued presence of agonist, a longer (100 ms) pressure pulse was applied in BLA neurons. The rise-time was 16 ± 6 ms, while the half-time of decay for the onset of desensitization was 42 ± 8 ms (n = 6) (Fig. 3C).

Current responses were graded in amplitude when the duration of pressure pulses was varied. Peak response amplitudes averaged −38 ± 12 pA for 5 ms duration pulses, −75 ± 17 pA for 10 ms pulses, −110 ± 17 pA for 15 ms pulses, and −89 ± 17 pA for 100 ms pulses (n = 6 BLA neurons).

Distribution of nAChRs in LA and BLA neurons through mapping via local photolysis of caged carbachol

Laser photolysis of caged carbachol (cCarb) was used to examine the distribution of functional nAChRs in neurons within the basolateral complex. cCarb (500 μm) was continuously perfused at a rate of 10 μl min−1, and nAChR responses were focally elicited by applying a UV laser pulse for 15 ms. The laser was positioned on the soma as well as dendrites that were visualized using a fluorescent dye and confocal microscope (see Methods). Although BLA neurons express functional muscarinic ACh receptors (Washburn & Moises, 1992), we have determined previously that carbachol-induced responses under these experimental conditions do not activate these receptors (Khiroug et al. 2003).

A representative LA neuron and plot of the current amplitude versus the distance from the soma is presented in Fig. 4. The average peak amplitude for cCarb uncaging responses on the soma was −58 ± 9 pA (n = 9; 7 for BLA and 2 for LA neurons), and peak responses generally decreased as the distance from the soma increased. This indicates that functional nAChRs are expressed both on the soma and dendrites of neurons in the amygdala, and suggests that they may be playing a postsynaptic role in cholinergic transmission.

Figure 4. Mapping of functional nAChRs in amygdala neurons by focal UV laser photolysis of caged carbachol.

Figure 4

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A, representative LA neuron showing the location and corresponding current response elicited by uncaging of caged carbachol (500 μm) on the soma and dendrites. Scale bar, 50 pA, 100 ms. B, plot of the percentage current (relative to soma) versus distance from the soma from a total of 9 responsive neurons (7 for BLA, and 2 for LA neurons).

Discussion

Here we have shown, for the first time, the presence of functional somato-dendritic nAChRs within the amygdala complex. The pressure application of ACh evoked rapidly activating and desensitizing currents in both the LA and BLA neurons, although BLA neurons were more responsive than LA neurons. In addition to the fast kinetic properties of these responses, the complete block by the α7-selective antagonist MLA, as well as the activation by the α7-selective agonist choline, indicates that α7-containing nAChRs are the predominant subtype expressed in these neurons. The focal activation of nAChRs via UV laser-induced photolysis of cCarb demonstrates that these receptors are functionally expressed on both the soma and dendrites. Although ACh induced single action potential firing in 20% of BLA neurons, in most cases the depolarization was not sufficient to induce firing of the neurons on its own, and therefore the activation of these receptors is likely to serve more in a modulatory role. Furthermore, neither glutamate release (either through the activation of presynaptic nAChRs on glutamatergic terminals or co-release with ACh), nor glutamate receptor activation, appear to be involved in these α7-nAChR-mediated responses.

Previous binding and immunocytochemistry studies have established the presence of nAChRs within the amygdala, yet their functional significance here remains to be elucidated. To date, reports describing the functional role of nAChR modulation in the amygdala have been limited to their presence at presynaptic terminals, where they can modulate glutamatergic and/or GABAergic synaptic transmission. In olfactory bulb/amygdala cocultures, the facilitation of both glutamatergic and GABAergic synaptic transmission was sensitive to the α7-selective antagonist α-bungarotoxin, suggesting a role for α7-containing receptors (Barazangi & Role, 2001). In recordings from BLA neurons in slices, ACh increased spontaneous GABAergic IPSCs by activating α3β4-containing nAChRs (Zhu et al. 2005). Therefore, different nAChR subtypes appear to be playing distinct functional roles within the amygdala complex.

Based on morphology and firing properties, two to three main types of neurons in the LA and BLA nuclei have been described (Sah et al. 2003): (1) pyramidal spiny or class I cells thought to be glutamatergic, and have broad action potentials and show spike frequency adaptation (although to varying degrees), and comprising ∼95% of the neurons; (2) non-spiny stellate or class II cells, which are local circuit GABAergic interneurons and have short-duration action potentials and little to no spike frequency adaptation; and (3) a group referred to as single firers and comprising only ∼3% of the neurons (McDonald & Augustine, 1993; Smith & Paré, 1994). However, more recently, Faber et al. (2001) found that pyramidal neurons have firing patterns that vary significantly, without any correlation between firing properties and morphology. In the present study, we observed spiking patterns that were consistent with the pyramidal class I neurons (the major neuronal type in both the LA and BLA nuclei); most neurons had regular-spiking action potential firing properties, although there was variability in spiking patterns among the neurons examined. In addition, we found no correlation between firing frequency and the response to ACh, suggesting that nAChRs are expressed on several subtypes of these neurons, and not restricted to specific subtypes. Other techniques (e.g. immunocytochemistry) will be needed to further identify the subtypes of neurons in the basolateral amygdala complex that express functional nAChRs.

The presence of functional fast-gating α7-containing nAChRs in BLA and LA neurons provides a possible mechanism for the rapid excitation of these neurons by the cholinergic projections from the nucleus basalis magnocellularis (Sah et al. 2003) into the amygdala. Presently, we do not know whether these receptors are located at synapses, and/or extrasynaptically, or whether they can be activated synaptically by endogenous ACh. However, this is a distinct possibility since the electrical stimulation of the nucleus basalis activates postsynaptic muscarinic ACh receptors on BLA neurons due to the release of endogenous ACh (Washburn & Moises, 1992). Nevertheless, such a fast mechanism would be in addition to previous reports that presynaptic nAChRs (both α7 and non-α7 receptors) regulate both glutamatergic as well as GABAergic synaptic transmission (Barazangi & Role, 2001; Zhu et al. 2005). Thus nAChRs appear to have profound effects on regulating excitability in the amygdala. It will be important to determine the downstream consequences of nAChR activation since this is likely to be the causal link whereby nicotine in the BLA nucleus regulates passive avoidance performance and enhances short- and long-term memory formation (Blozovski & Dumery, 1987; Barros et al. 2005), while inhibitors cause significant memory impairment (Addy et al. 2003; Barros et al. 2005).

In conclusion, the expression of functional somato-dendritic α7 nAChRs in neurons from rat amygdala slices suggests a new potential mechanism whereby these receptors are significantly involved in mediating fear and aversively motivated memory processes. This information is critical as it might provide insight into the basic mechanisms involved in various human disorders, such as anxiety, schizophrenia, epilepsy, addiction and autism (Newhouse et al. 2004; Giniatullin et al. 2005; Lippiello, 2006). In addition, these data suggest that some effects of nicotine on behaviour are linked to the presence of these nAChRs on amygdala neurons. Further investigations into the role of somato-dendritic nAChRs will be very important from a therapeutic standpoint in order to aid in the design of therapeutics to treat these devastating conditions.

Acknowledgments

We would like to thank C. Erxleben and S. Dudek for advice in preparing the manuscript. Research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We are also grateful to Scott Moore and Jennifer Naylor for their assistance with experimental procedures for preparing amygdala slices.

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