Distributions of nicotinic acetylcholine receptor α7 and β2 subunits on cultured hippocampal neurons

Zarei, Masoud; Radcliffe, Kristofer A.; Chen, D; Patrick, James W.; Dani, John A.

doi:10.1016/s0306-4522(98)00246-2

Cited by 102 publications

(97 citation statements)

References 58 publications

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“…As illustrated in Figure 3C, PNU-120596 failed to potentiate the ACh-evoked response when measured in the presence of MLA (n ϭ 3). The cell used for this example was typical of most cultured hippocampal neurons and predominantly expressed MLA-sensitive ACh-evoked currents (Alkondon and Albuquerque, 1993;Zarei et al, 1999). Thus, these data, in combination with the results shown in Figure 2 D, provide good evidence that PNU-120596 enhanced the function only of nAChRs containing the ␣7 subunit.…”

Section: Pnu-120596 Selectively Enhances the Function Of ␣ 7 Nachrssupporting

confidence: 53%

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Hurst¹,

Hajós²,

Raggenbass³

et al. 2005

J. Neurosci.

422

473

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Several lines of evidence suggest a link between the ␣7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the ␣7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human ␣7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by ␣4␤2, ␣3␤4, and ␣9␣10 nAChRs. PNU-120596 increased the channel mean open time of ␣7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of ␣7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances ␣7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.

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Section: Pnu-120596 Selectively Enhances the Function Of ␣ 7 Nachrssupporting

confidence: 53%

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Hurst¹,

Hajós²,

Raggenbass³

et al. 2005

J. Neurosci.

422

473

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“…Summation of the platform-induced stress and the nicotine-induced corticosterone release may interfere with environmental familiarization. Indeed, corticosterone receptors and nicotinic ACh receptors are colocalized in the hippocampus (Morimoto et al, 1996;Takahashi, 1996;Zarei et al, 1999). This brain structure is widely implicated in learning and memory (e.g., Levin & Simon, 1998;McNaughton & Morris, 1987;Ohno et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Environmental Familiarization in Rats: Differential Effects of Acute and Chronic Nicotine

Bevins

Koznarova

Armiger

2001

Neurobiology of Learning and Memory

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_________________________________________________________If an environment is familiar, rats will interact more with a novel object than if the environment is unfamiliar. In two experiments we used this behavioral tendency to assess the effects of nicotine on environmental familiarization (i.e., an elevated platform). As expected, rats given 2 min of exposure to the platform on 2 consecutive days (familiarization phase) interacted more with a novel object in a subsequent test than rats that had not experienced the platform until the test day. During the familiarization phase acute pretreatment with nicotine (0.6 and 1.8 mg/kg, subcutaneous) 10 min before platform exposure interfered with familiarization processes, as measured by object interaction on the drug-free test day. Behavioral measures of activity (e.g., turning and midline crosses) eliminated an account based on nicotine-induced motor impairment. Furthermore, this effect of acute nicotine on familiarization was not due to nonspecific effects of nicotine. Controls that received equivalent nicotine exposure temporally separated from platform exposure interacted more with the novel object than similarly treated controls that were unfamiliar with the platform on the test day. Interestingly, rats treated once daily with 0.6 mg/kg nicotine for 14 days before the familiarization phase (chronic condition) did not show a decrease in environmental familiarity. This dissociation extends a growing literature finding that the behavioral and neurobiological effects of nicotine differ, in part, after acute and chronic exposure. Indeed, acute nicotine (0.2, 0.6, and 1.2 mg/kg) in the present report consistently decreased the amount of time spent with one paw on the edge of the platform; chronic nicotine did not affect this behavior.

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“…Correlation between dendritic length and ␣7* nAChR activity evoked by exogenous application of choline to CA1 SR interneurons in 21-d-old WT and mKat-2 ؊/؊ mice Previous studies have shown that ␣7* nAChR density increases along with dendritic length in hippocampal neurons in culture (Albuquerque et al, 1997;Zarei et al, 1999) and decreases along the dendrites of hippocampal CA1 interneurons in slices (Khiroug et al, 2003). To determine whether increased ␣7* nAChR activity in CA1 SR interneurons of mKat-2 Ϫ/Ϫ mice was accompanied by changes in dendritic length in these neurons, two approaches were taken.…”

Section: Characterization Of Nicotinic Responses Recorded From Ca1 Srmentioning

confidence: 99%

Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission viaα7 Nicotinic Receptors in the Hippocampus

Alkondon¹,

Pereira²,

Yü³

et al. 2004

J. Neurosci.

125

113

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It has been postulated that endogenous kynurenic acid (KYNA) modulates ␣7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.a To test this hypothesis, ␣7* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2 ؊/؊ mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2 ؊/؊ mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, ␣7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was ϳ65% higher in mKat-2 ؊/؊ than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in ␣7* nAChR number. In 21-d-old mKat-2 ؊/؊ mice, endogenous ␣7* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABA A and NMDA receptors in the interneurons and of ␣3␤4* nAChRs regulating glutamate release onto these neurons were comparable between mKat-2 ؊/؊ and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2 ؊/؊ and WT mice. Our findings that ␣7* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and ␣7* nAChR functions are impaired.

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Distributions of nicotinic acetylcholine receptor α7 and β2 subunits on cultured hippocampal neurons

Cited by 102 publications

References 58 publications

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Environmental Familiarization in Rats: Differential Effects of Acute and Chronic Nicotine

Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission viaα7 Nicotinic Receptors in the Hippocampus

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