How Does the Brain Store Memories?
Experience changes the strength and number of synaptic connections between neurons in the brain. This process, known as synaptic plasticity, provides a cellular mechanism for memory storage. Research in the Martin lab is aimed at understanding the cell and molecular biology of synaptic plasticity in mouse and Aplysia model systems. The results of their research shed light not only on healthy brain function, but also on the causes of many brain disorders in which neuronal plasticity and memory formation are altered, including mental retardation, autism spectrum disorders, drug addiction, anxiety disorders, and Alzheimers disease.
Long-term forms of plasticity, such as those underlying long-term memory, require new RNA and protein synthesis. This means that signals are transported from the synapse, where they are generated, to the nucleus, where they alter transcription. The transport of molecules from the synapse to the nucleus of neurons is particularly challenging because synapses are often very far from the cell body. The Martin lab has discovered a role for the active transport of signals from stimulated synapses to the nucleus during long-term neuronal plasticity. Current research is aimed at identifying synaptically localized signaling molecules that undergo stimulus-induced active nuclear import during plasticity, and at understanding the cell biological pathways that mediate long-distance retrograde transport from synapse to nucleus. In studies focused on the transcriptional regulator CRTC1, the Martin lab is exploring how specific patterns of neuronal stimulation trigger specific programs of transcription, and how neuromodulators such as dopamine and norepinephrine regulate the programs of gene expression that give rise to long-lasting plasticity. This work provides molecular insights into the role of emotion and attention in memory formation.
Research in the Martin lab also addresses the mechanisms by which transcription-dependent plasticity can occur at subsets of the thousands of synapses that are made by an individual neuron. Dr. Martin and her colleagues have shown that one important mechanism for restricting gene expression to stimulated synapses involves the regulated translation of synaptically localized mRNAs. Studies in her lab are aimed at identifying the populations of mRNAs that localize to synapses, the molecular mechanisms underlying the localization and translation of these mRNAs, as well as the function of local translation in long-term memory. Recent transcriptome and translatome profiling experiments suggest that the regulation of gene expression in neurons is highly decentralized and compartmentalized during plasticity, with transcriptional regulation placing the entire neuronal arbor in a state of readiness to respond to local cues via local translation to change the structure and function of subsets of synapses.
A selected list of publications:
Dzudzor Bartholomew, Huynh Lucia, Thai Minh, Bliss Joanne M, Nagaoka Yoshiko, Wang Ying, Ch'ng Toh Hean, Jiang Meisheng, Martin Kelsey C, Colicelli John
Regulated expression of the Ras effector Rin1 in forebrain neurons
Molecular and cellular neurosciences,
Lyles, V., Zhao, Y. and Martin, K.C.
Synapse formation and mRNA localization in Aplysia sensory-motor neurons,
Ormond, J Hislop, J Zhao, Y Webb, N Vaillaincourt, F Dyer, JR Ferraro, G Barker, P Martin, KC Sossin, WS
ApTrkl, a Trk-like receptor, mediates serotonin- dependent ERK activation and long-term facilitation in Aplysia sensory neurons
Ormond Jake, Hislop Jonathan, Zhao Yali, Webb Neil, Vaillaincourt Francois, Dyer John R, Ferraro Gino, Barker Phil, Martin Kelsey C, Sossin Wayne S
ApTrkl, a Trk-like receptor, mediates serotonin- dependent ERK
activation and long-term facilitation in Aplysia sensory neurons
Martin, K.C. and Sun, Y.I
To Learn Better, Keep Your HAT On,
Moccia, R Chen, D Lyles, V Kapuya, E E, Y Kalachikov, S Spahn, CM Frank, J Kandel, ER Barad, M Martin, KC
An unbiased cDNA library prepared from isolated Aplysia sensory neuron processes is enriched for cytoskeletal and translational mRNAs
The Journal of Neuroscience. ,
Moccia Robert, Chen Dillon, Lyles Vlasta, Kapuya Estreya, E Yaping, Kalachikov Sergey, Spahn Christian M T, Frank Joachim, Kandel Eric R, Barad Mark, Martin Kelsey C
An unbiased cDNA library prepared from isolated Aplysia sensory neuron
processes is enriched for cytoskeletal and translational mRNAs
The Journal of neuroscience : the official journal of the Society for Neuroscience,
Martin, K.C., and Kosik, K.S
Synaptic Tagging - Who's it?,
Nature Neurosci. Rev,
Patterson, S.L., Pittenger, C., Morozov, A., Martin, K.C., Scanlin, H., Drake, C., and Kandel, E.R
Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase,
Martin, K.C., Bartsch, D., Bailey, C.H. and Kandel,E.R.
Molecular mechanisms underlying learning-related long-lasting synaptic plasticity,
The New Cognitive Neurosciences,
2000; 2nd edition:
Casadio, A.*, Martin, K.C.*, et al.
A novel, transient form of CREB-mediated long-term facilitation that is neuron-wide and can be stabilized at specific synapses by local rapamycin-sensitive protein synthesis,
Winder, D.G., Martin, K.C., Muzzio, I., Rohrer, D., Chruscinski, A., Kobilka, B. and Kandel, E.R.
ERK plays a novel role in the induction of LTP by theta frequency stimulation and its regulation by beta-adrenergic receptors in CA1 pyramidal cells,
Martin, KC Casadio, A Zhu, H Yaping, E Rose, JC Chen, M Bailey, CH Kandel, ER
Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage