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7 Nicotinic Acetylcholine Receptors Occur at Postsynaptic Densities of AMPA Receptor-Positive and -Negative Excitatory Synapses in Rat Sensory Cortex

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7 Nicotinic Acetylcholine Receptors Occur at Postsynaptic Densities of AMPA Receptor-Positive and -Negative Excitatory Synapses in Rat Sensory Cortex The Journal of Neuroscience, June 15, 2002, 22(12):5001–5015 ␣7 Nicotinic Acetylcholine Receptors Occur at Postsynaptic Densities of AMPA Receptor-Positive and -Negative Excitatory Synapses in Rat Sensory Cortex Robert B. Levy and Chiye Aoki New York University Center for Neural Science, New York, New York 10003 NMDA receptor (NMDAR) activation requires concurrent mem- over most of the thick postsynaptic densities in all cortical brane depolarization, and glutamatergic synapses lacking layers of both age groups. AMPAR immunoreactivity was also AMPA receptors (AMPARs) are often considered “silent” in the detectable at most synapses; its distribution was independent absence of another source of membrane depolarization. During of that of ␣7nAChR. In both age groups, approximately one- the second postnatal week, NMDA currents can be enhanced in quarter of asymmetrical synapses were ␣7nAChR positive and rat auditory cortex through activation of the ␣7 nicotinic ace- AMPAR negative. The variability of postsynaptic ␣7nAChR la- tylcholine receptor (␣7nAChR). Electrophysiological results beling density was greater at postnatal day (PD) 7 than in support a mainly presynaptic role for ␣7nAChR at these syn- adulthood, and PD 7 neuropil contained a subset of small apses. However, immunocytochemical evidence that ␣7nAChR AMPA receptor-negative synapses with a high density of is prevalent at postsynaptic sites of glutamatergic synapses in ␣7nAChR immunoreactivity. These observations support the hippocampus and neocortex, along with emerging electrophys- idea that acetylcholine receptors can aid in activating glutama- iological evidence for postsynaptic nicotinic currents in neocor- tergic synapses and work together with AMPA receptors to tex and hippocampus, has prompted speculation that mediate postsynaptic excitation throughout life. ␣7nAChR allows for activation of NMDAR postsynaptically at synapses lacking AMPAR. Here we used dual immunolabeling Key words: sensory cortex; receptive field properties; ␣7 and electron microscopy to examine the distribution of nicotinic acetylcholine receptor; glutamate; AMPA receptor; ␣7nAChR relative to AMPAR (GluR1, GluR2, and GluR3 sub- NMDA receptor; synaptic plasticity; early postnatal develop- units combined) at excitatory synapses in somatosensory cor- ment; postsynaptic density; immunocytochemistry; electron tex of adult and 1-week-old rats. ␣7nAChR occurred discretely microscopy Plasticity of receptive field properties in sensory cortex depends specifically at synapses of neonatal cortex lacking AMPA recep- on experience-dependent modification of glutamatergic pathways tor (AMPAR) activity (Aramakis and Metherate, 1998; Ara- (Kleinschmidt et al., 1987; Fox et al., 1996; Rasmusson, 2000) and makis et al., 2000). cholinergic modulation of these pathways (Bear and Singer, 1986; Despite its prevalence, the role of ␣7nAChR in modulating Sillito and Murphy, 1987; Mu¨ller and Singer, 1989; Baskerville et excitatory transmission and long-term synaptic changes is unclear. al., 1997; Kilgard and Merzenich, 1998). Although developmental Much of the physiological effect of nicotine apparently results studies have focused on muscarinic acetylcholine receptors, re- from presynaptic modulation of glutamatergic pathways, i.e., en- cent knowledge regarding central nicotinic receptors, particularly hanced glutamate release (McGehee et al., 1995; Role and Berg, the ␣7 nicotinic acetylcholine receptor subunit (␣7nAChR), in- 1996; Jones et al., 1999). However, electrophysiological evidence dicates that these too are important for synaptic plasticity. Spe- exists for direct activation of postsynaptic nAChR in hippocam- cifically, ␣7nAChR subunits (1) form homo-oligomeric channels pus (Alkondon et al., 1998; Frazier et al., 1998a,b; Hefft et al., ϩ with greater Ca 2 permeability than NMDA receptor 1999) and neocortex (Roerig et al., 1997; Chu et al., 2000). Also, (NMDAR) (McGehee, 1999), (2) are prevalent during the first previous immunocytochemical results showed a primarily soma- postnatal week, before onset of the critical period for experience- todendritic distribution of ␣7nAChR within neocortical and hip- dependent developmental plasticity (Fuchs, 1989; Bina et al., pocampal pyramidal neurons (Dominguez del Toro et al., 1994). 1995; Broide et al., 1995), and (3) enhance NMDA currents Past EM immunocytochemical work by us and others agrees with these immunocytochemical findings: ␣7nAChR is concen- Received Dec. 12, 2001; revised March 13, 2002; accepted March 22, 2002. trated at postsynaptic sites of asymmetric synapses in cortex This research was supported by National Institutes of Health (NIH) Grants R01 (Lubin et al., 1999) and hippocampus (Fabian-Fine et al., 2001). NS41091 and R01 NEI 13145-01 to C.A., and NIH P30 EY13079 core grant, National Institute of Mental Health Training Grant 5T32MH195424-10, and Office These synapses are presumably excitatory (Gray, 1959; Altschuler of Naval Research Solicitation No. 99-019 to the Center for Neural Science. We et al., 1984; Somogyi et al., 1986; Aoki et al., 1991). Although this thank Claudia Farb, Mona Lubin, and Veeravan Mahadomrongkul for discussion suggests that some of the direct or indirect effects of nicotine and technical assistance. The work described in this paper was presented at the Society for Neuroscience occur via postsynaptic glutamate receptors, morphology alone 31st annual meeting, San Diego, CA, November 10–15, 2001 (abstract 362.15). cannot reveal the glutamate receptor subtypes at these Correspondence should be addressed to Chiye Aoki, New York University Cen- ␣ ter for Neural Science, 4 Washington Place, Room 809, New York, NY 10003. 7nAChR-immunopositive synapses. Immunocytochemical stud- E-mail: [email protected]. ies of hippocampus indicate that NMDARs are present in most Copyright © 2002 Society for Neuroscience 0270-6474/02/225001-15$15.00/0 asymmetric synapses throughout postnatal development, whereas 5002 J. Neurosci., June 15, 2002, 22(12):5001–5015 Levy and Aoki • Postsynaptic ␣7 nAChR and AMPA Receptors in Rat Sensory Cortex AMPARs are acquired selectively (Nusser et al., 1998; Kharazia of cortical layers under the electron microscope. Portions of each section and Weinberg, 1999; Liao et al., 1999; Petralia et al., 1999; Shi et spanning all layers of S1 cortex were capsule embedded, and 70–90 nm sections were cut on an MT-7 ultramicrotome (RMC, Tucson, AZ) and al., 1999). These results complement physiological evidence from collected on Formvar-coated grids. Grids were then subjected to postem- hippocampus (Isaac et al., 1995; Liao et al., 1995; Durand et al., bedding ␣7nAChR labeling (see below) or viewed directly using a JEOL 1996) and neocortex (Wu et al., 1996; Isaac et al., 1997; Rumpel 1200 XL electron microscope (JEOL Inc., Tokyo, Japan). et al., 1998) that many NMDAR-containing synapses lack Postembedding immunocytochemistry for ␣7nAChR. ␣7nAChR labeling AMPAR function early in development. These synapses are was performed by the postembedding gold (PEG) procedure of Erisir et al. (1997) modified from that of Phend et al. (1992). Conditions were often considered physiologically “silent” without the local depo- adjusted to gain optimal detection of ␣7nAChR by PEG while maintain- larization required for NMDAR activity (Feldman et al., 1999). ing high-quality ultrastructural preservation (particularly of membranes) Might ␣7nAChR contribute to postsynaptic activation of these and preservation of HRP–DAB reaction product corresponding to synapses? To address this question, we examined the distribution AMPAR subunit immunoreactivity. Mouse monoclonal antibody 306, ␣ of ␣7nAChR relative to AMPARs at asymmetric synapses in directed against a predicted cytoplasmic domain of 7nAChR (Scho- epfer et al., 1990; McLane et al., 1992), was obtained from Research neonatal and adult rat somatosensory cortex. EM immunocyto- Biochemicals International (Natick, MA) and used at a dilution of 1:250. chemistry was used to resolve the presynaptic versus postsynaptic This antibody was used previously in a light microscopic study of location of ␣7nAChR and to determine whether the presence of ␣7nAChR distribution in adult rat brain (Dominguez del Toro et al., ␣7nAChR at nascent synapses precedes the arrival of AMPARs. 1994) and more recently in an EM study of adult rat hippocampus CA1 (Fabian-Fine et al., 2001). In the latter instance, the specificity of synaptic labeling with monoclonal antibody (mAb) 306 was confirmed by the use MATERIALS AND METHODS of a polyclonal antibody directed against a region containing the same epitope; mitochondrial labeling seen with mAb 306 was shown to be a Tissue preparation. Adult (200–300 gm) and postnatal day (PD) 7 lower-specificity reaction with a species of 48 kDa, smaller than the Sprague Dawley rats were deeply anesthetized with sodium pentobarbital ␣ (50 mg/kg body weight) and then perfused transcardially with a mixture native molecular mass of the 7nAChR subunit. Incubation time in primary antibody was 2.5 hr; the inclusion of 0.1% Triton X-100 in the of 1% glutaraldehyde and 4% paraformaldehyde in 0.1 M phosphate buffer (PB), pH 7.4. Brains were postfixed by immersion at room tem- incubation mixture to remove osmium and enhance antibody penetration perature (RT) for 1 hr (for adults) or overnight (for PD 7) in the same allowed us to avoid etching steps that cause severe deterioration of fixative. The prolonged postfixation for neonatal brains was included to ultrastructure (Phend et al., 1992). Longer incubation times
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