Chiye Aoki

Neuronal Plasticity in Neocortex

The goal of my research is to understand the cell biological mechanisms underlying plasticity and stability of neurons. The mammalian brain undergoes dramatic developmental changes after birth to attain neural functions that reflect the experience of early life. Once mature, the pathways of the brain become more stable while maintaining a certain degree of plasticity. I am investigating how catecholamines and acetylcholine in the neocortex regulate plasticity via interactions with amino acid neurotransmitters during postnatal development and in adulthood.

My research while a graduate fellow in the laboratory of Dr. Philip Siekevitz at the Rockefeller University showed that there is a functional link between neuronal activity, second messengers, and phosphorylation of a cytoskeletal protein--MAP2--during the critical period for visual cortex development. These results suggest that neuronal plasticity may depend on the malleability of cell shape, which, in turn, is dependent on the state of phosphorylation of cytoskeletal proteins. For this work, I received a Ph.D. degree in 1985.

For my postdoctoral training, I joined the laboratory of Dr. Virginia M. Pickel at the Department of Neurology and Neuroscience, The Cornell University Weill Medical College, where I learned how to visualize two types of molecules simultaneously at a level of resolution afforded by an electron microscope, so that molecular interactions at newly forming and well- established synapses could be probed. Using this technique, I have shown that (1) catecholamines diffuse beyond the synaptic cleft to activate receptors at sites that lack ultrastructural features of synapses; (2) glia extend fine processes around glutamatergic synapses to aid in converting neuronally released glutamate to its non-toxic form, glutamine; (3) the novel neuronal messenger--nitric oxide--can be generated both pre- and postsynaptically and within spines expressing NMDA receptors; and (4) NMDA receptors occur both pre- and postsynaptically; (5) NMDA receptor clusters can be found at nonsynaptic sites of dendritic shafts and somata during early life, prior to the arrival of afferents.

My current research continues to use electron microscopic techniques to examine the cellular bases of interaction between transmitters and receptors that are thought to have important roles in synaptic plasticity. By using the electron microscope, we have observed that neurotransmitter receptors are brought to the pre- and postsynaptic membrane in an activity-dependent manner. This response is measurable within tens of minutes within adult cortices. We have a hunch that cytoskeletal proteins are involved in the activity-dependent trafficking of synaptic molecules within dendritic spines and axon terminals. Thus, we are exploring the impact of the appearance or removal of two candidate molecules that link the recruitment of synaptic molecules to newly forming synapses: drebrin, for the postsynaptic membrane and neurexin, for the axon terminals.

Another interest of mine is to understand the cellular and molecular mechanisms underlying cholinergic modulation. Why are there so many different types of acetylcholinergic receptors in the brain? Even a single layer of the cortex contains at least four different types of acetylcholine receptors. We are exploring the possibility that the various types of acetylcholine receptors may be distributed in a pathway-specific manner within single brain regions, thereby allowing for multifaceted mode of modulation of excitatory and inhibitory synapses. Our method of approach is to combine electrophysiological measurements of neuronal responses to the application of receptor-specific agonists and antagonists and then to relate this activity pattern to the ultrastructural distribution of cholinergic receptor proteins at pathway-specific synapses.

E-mail: chiye@cns.nyu.edu

Representative Publications

C. Aoki and P. Siekevitz. December 1988. Plasticity in brain development. Scientific American. 256(12): 56-64.

C. Aoki and S. Kabak. 1992. Cholinergic terminals in the cat visual cortex: Ultrastructural basis for interaction with glutamate-immunoreactive neurons and other cells, Visual Neurosci., 8: 177-191.

C. Aoki, M. Lubin and F. Fenstemaker. 1994. Columnar regulation of β-adrenergic receptor-like immunoreactivity in monkey V1.Vis. Neurosci. 11: 179-187.

C. Aoki. 1997. Immunoelectron microscopy reveals differential timing for the appearance of neuronal and astrocytic beta-adrenergic receptors in the developing rat cerebral cortex, Vis. Neurosci. 14: 1129-1142.

M. Lubin, C. S. Leonard and C. Aoki. 1997. Preservation of ultrastructure and antigenicity for EM immunocytochemistry following intracellular recording and labeling of single cortical neurons in brain slices. J. Neurosci. Methods, 81: 91-102.

Aoki C, Bredt DS, Fenstemaker S and Lubin M (1998) The subcellular distribution of nitric oxide synthase relative to the NR1 subunit of NMDA receptors in the cerebral cortex. In Prog in Brain Res 118 Nitric Oxide in Brain Development, Plasticity, and Disease, RR Mize, TM Dawson, VL Dawson and MJ Friedlander, eds., 83-100.

C. Aoki, S. Rodrigues and H. Kurose. 1999. Use of electron microscopy in the detection of adrenergic receptors. In Methods in Molecular Biol: Adrenergic Receptor Protocols, 136: 537- 565, C Machida, ed., Humana..

Erisir, A. I Levey and C. Aoki (2001) Muscarinic receptor M2 in cat visual cortex: laminar distribution, relationship to GABAergic neurons and effect of cingulate lesions. J Comp Neurol 441: 168-185.

C Aoki, I Mkio, H Oviedo, T Mikeladze-Dvall, L Alexandre, N Sweeney and DS Bredt. (2001) Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102 and SAP-97 at postsynaptic, presynaptic and nonsynaptic sites of adult and neonatal rat visual cortex. Synapse 40: 239-257.

RB Levy and C Aoki. (2002) Alpha7 nicotinic acetylcholine receptors occur at postsynaptic densities of AMPA receptor-positive and negative excitatory synapses in rat sensory cortex. J Neurosci , 22: 5001-5015.

Weizhi Chen, Veeravan Mahadomrongkul, Urs V. Berger, Merav Bassan, Tara DeSilva, Kohichi Tanaka,Nina Irwin, Chiye Aoki, and Paul A. Rosenberg (2004) The Glutamate Transporter GLT1a is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons. J Neurosci, 24: 1136-48.

C Aoki, Y Sekino, K Hanamura, V Mahadomrongkul, S Fujisawa, Y Ren and T Shirao (2005) Drebrin A is a postsynaptic protein that localizes in vivo to the submembranous surface of dendritic sites forming excitatory synapses. J Comp Neurol., 483:383-402

EH Chang, MJ Savage, DG Flood, JM Thomas, RB Levy, V Mahadomrongkul, T Shirao, C Aoki and PT Huerta. (2005) AMPA receptor downscaling at the onset of Alzheimer's pathology in double knock-in mice. Proc Natl Acad Sci., 103:3410-3415

R Levy, A Reyes and C Aoki (2006) Nicotinic and muscarinic reduction of unitary excitatory postsynaptic potentials in sensory cortex; dual intracellular recording. J Neurophysiol. 95(4):2155-66.

Sho Fujisawa, T Shirao and C Aoki (2006) In vivo, competitive blockade of NMDA receptors induces changes in F-actin and drebrin A distributions within dendritic spines of adult rat cortex. Neuroscience 140(4):1177-87. doi:10.1016/j.neuroscience.2006.03.009 

Taniguchi H, Gollan L, Scholl FG, Mahadomrongkul V, Dobler E, Limthong N, Peck M, Aoki C and Scheiffele P. (2007) Silencing of neuroligin function by postsynaptic neurexins. J Neurosci 27: 2815-24. DOI:10.1523/JNEUROSCI.0032-07.2007

C. Aoki, V. Mahadomrongkul, S Fujisawa, R Habersat and T Shirao. 2007. Chemical and morphological alterations of spines within the hippocampus and entorhinal cortex precede the onset of Alzheimer's disease pathology in double knock-in mice. J Comp. Neurol. 505: 352-362. DOI 10.1002/cne.21485

Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, Williams K, Smith SS (2007) Reversal of neurosteroid effects at alpha4beta2delta GABA(A) receptors triggers anxiety at puberty. Nat Neurosci 10: 469-77. doi:10.1038/nn1868

A. Disney, C. Aoki and MJ Hawken. (2007) Gain modulation by nicotine in Macaque V1. Neuron 56: 701-713. DOI 10.1016/j.neuron.2007.09.034

A Disney and C Aoki. Muscarinic acetylcholine receptors in macaque V1 are most frequently expressed by parvalbumin-immunoreactive neurons. (2007) J Comp Neurol, 507: 1748-1762. DOI 10.1002/cne.21616

E.C. Sarro, V. C. Kotak, D. H Sanes and C. Aoki. (2008) Hearing loss alters the subcellular distribution of presynaptic GAD and postsynaptic GABAA receptors in the auditory cortex. Cerebral Cortex, 18: 2855-67. 10.1093/cercor/bhn044

RB Levy, AD Reyes and C Aoki (2008) Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex. Brain Research 1215: 97-104. doi:10.1016/j.brainres.2008.03.067

A complete list of my publications