Dr. Alfredo Kirkwood is a professor of neuroscience at the Johns Hopkins School of Medicine. His research focuses on the mechanisms of cortical modification.
His team is researching how synaptic inhibition and the action of neuromodulators regulate the induction of long-term potentiation (LTP) and long-term depression (LTD) during development.
Dr. Kirkwood received his MS from the Universidad de Chile and his PhD from Brandeis University.
Mechanisms of Cortical Modification
Sensory experience has a profound influence in shaping the functional organization of the cerebral cortex. Over 30 years ago, Hubel and Wiesel described a critical period of postnatal development for the formation of binocular connections in cat visual cortex. They demonstrated that thisconnectivity can be dramatically altered by simple forms of sensory deprivation, such as the temporary closure of one eyelid (monoculardeprivation). Besides the obvious relevance of this neural plasticity to the development of visual capabilities in humans and animals, it seems likely hat similar processes form the basis for some forms of learning and memory in the adult brain. Indeed, visual cortical plasticity, like learning andmemory formation decreases with age and depend on the internal state of the animal. The research in this lab is directed toward elucidating thebasic mechanisms by which visual experience can modify cortical connections in the visual cortex, and how those mechanisms are regulated.
We investigate in visual cortical slices two forms of activity-dependent synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD). These two forms of synaptic plasticity are currently the most comprehensive models of the elementary mechanisms underlying naturallyoccurring plasticity. Research done the past few has established that LTP and LTD have the appropriate properties to account for important features of naturally-occurring synaptic modification in visual cortex. Furthermore, changes in LTP and LTD during development correlate withchanges in naturally-occurring synaptic modification.
We are currently focused on how synaptic inhibition and the action of neuromodulators regulate the induction of LTP and LTD duringdevelopment. The results of these investigation suggest two hypotheses. 1) The development of synaptic inhibition restricts the induction of LTPand LTD, and henceforth, the modification by experience to a short critical period. 2) The action of neuromodulators released during arousal is to enhance the induction LTP and LTD by orders of magnitude, thus enabling experience to modify the visual cortex. Our expectation is that by testing these specific hypothesis we are stand to gain a better understanding of how naturally occurring plasticity is regulated.
Gao M, Whitt JL, Huang S, Lee A, Mihalas S, Kirkwood A, Lee HK. Experience-dependent homeostasis of 'noise' at inhibitory synapses preserves information coding in adult visual cortex. Philos Trans R Soc Lond B Biol Sci. 2017;372(1715). pii: 20160156
Gu Y, Tran T, Murase S, Borrell A, Kirkwood A, Quinlan EM. Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period. J Neurosci. 2016;36:10285-10295
Wang H, Ardiles AO, Yang S, Tran T, Posada-Duque R, Valdivia G, Baek M, Chuang YA, Palacios AG, Gallagher M, Worley P, Kirkwood A. Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus. J Neurosci. 2016;36:1723-9
Huang S, Hokenson K, Bandyopadhyay S, Russek SJ, Kirkwood A. Brief Dark Exposure Reduces Tonic Inhibition in Visual Cortex. J Neurosci. 2015;3:15916-20
He K, Huertas M, Hong SZ, Tie X, Hell JW, Shouval H, Kirkwood A. Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron. 2015;88:528-38
Huang S, Rozas C, Treviño M, Contreras J, Yang S, Song L, Yoshioka T, Lee HK, Kirkwood A. Associative Hebbian synaptic plasticity in primate visual cortex. J Neurosci. 2014;34:7575-9
Huang S, Huganir RL, Kirkwood A. Adrenergic gating of Hebbian spike-timing-dependent plasticity in cortical interneurons. J Neurosci. 2013; 33:13171-8
Gu Y, Huang S, Chang MC, Worley P, Kirkwood A, Quinlan EM. Obligatory role for the immediate early gene NARP in critical period plasticity. Neuron. 2013;79(2):335-46
LeGates TA, Altimus CM, Wang H, Lee HK, Yang S, Zhao H, Kirkwood A, Weber ET, Hattar S. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature. 2012;491:594-8.
Guo Y, Huang S, de Pasquale R, McGehrin K, Lee HK, Zhao K, Kirkwood A. Dark exposure extends the integration window for spike-timing-dependent plasticity. J Neurosci. 2012;32:15027-35
Ardiles AO, Tapia-Rojas CC, Mandal M, Alexandre F, Kirkwood A, Inestrosa NC, Palacios AG. Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012;109:13835-40
Huang S, Treviño M, He K, Ardiles A, Pasquale Rd, Guo Y, Palacios A, Huganir R, Kirkwood A. Pull-push neuromodulation of LTP and LTD enables bidirectional experience-induced synaptic scaling in visual cortex. Neuron. 2012;73:497-510
Savonenko A, Muñoz P; Melnikova T, Wang Q, Liang X, Breyer R, Montine T, Kirkwood A, Andreasson (2009). Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor. J. Exp Neurol (in Press).
Lee HK, Min SS, Gallagher M, Kirkwood A. (2005) NMDA receptor-independent long-term depression correlates with successful aging in rats. Nat Neurosci. 2005 Dec;8(12):1657-9. Epub 2005 Nov 13.
Choi SY, Chang J, Jiang B, Seol GH, Min SS, Han JS, Shin HS, Gallagher M, Kirkwood A. (2005) Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex. J Neurosci. 2005 Dec 7;25(49):11433-43.
Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, Gouras GK, Kirkwood A, Morris RG, Shen J. (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 20;25(29):6755-64.
Jiang B, Huang ZJ, Morales B, Kirkwood A. (2005). Maturation of GABAergic transmission and the timing of plasticity in visual cortex. Brain Res Brain Res Rev. 50:126-33.
Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S. (2004). Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron. 42:773-87.
Saura, C., Choi, S.Y., Beglopoulos, C., Malkani, S., Zhang, D., Rao, S., Chattarji, S., Kelleher, R, Kandel, E., Duff, K., Kirkwood, A., and Shen. J. (2004). Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron 42: 23-36.
Morales, B, Choi SY, and Kirkwood, A. (2002). Dark rearing alters the development of GABAergic transmission in visual cortex. J. Neurosci. 22: 8084-90.
Choi, SY, Morales, B, Lee, HK, and Kirkwood, A. (2002) Absence of Long-Term Depression in the Visual Cortex of GAD 65 Knockout mice. J. Neurosci. 22, (5271-5276).
Rozas, C, Frank, H, Heynen, A. Morales, B. Bear, M. F. and Kirkwood, A. (2001) Developmental inhibitory gate controls the relay of activity to the superficial layers of the visual cortex J. Neurosci. 21, 6791-6801.
Yu, H. Saura, C. Choi, S.E. Sun, L. Yang, X Handler, M. Kawarabayashi, T Younkin, L. Wilson, M. Younkin, S. Kandel, E.R. Kirkwood, A. Shen. J (2001). APP Processing, Notch Signalling and Synaptic Synaptic Plasticity in the Adult Brain of Presenilin-1 Conditional Knockout Mice. Neuron 31, 713-726.
Frankland, P. W., O’Brien, C. O. Obne, M., Kirkwood, A & Silva, A. (2001) a-CAMKIII-dependent plasticity in the cortex is required for permanent memory traces. Nature 410, 309-313.
Kirkwood, A. Serotonergic control of developmental plasticity. (2000). Proc. Natl. Acad. Sci. (USA) 97, 1.
Huang, J., Z, Kirkwood, A., Morales, B., Pizzorusso, T. Porciatti, V., Bear, M. F., Maffei, L. & Tonegawa, S. (1999). BDNF is a key regulator of the maturation of inhibition and critical period of mouse visual cortex. Cell 98:739-755.
Kirkwood, A, Rozas, C., Kirkwood, J., Perez, F. and Bear M. F. (1999). Modulation of Long-Term Synaptic Depression in visual cortex by acetylcholine and norepinephrine. J. Neurosci. 1999 19: 1599-1609.
Kirkwood, A. Silva, A & Bear, M. F. (1997) Age-dependent decrease of synaptic plasticity in the neocortex of ?-CaM-KII mutant mice. Proc. Natl. Acad. Sci. (USA) 94, 3380-3383.
Kirkwood, A. , Rioult, M & M. F. Bear (1996) Experience-dependent modification of synaptic plasticity in rat visual cortex. Nature 381, 526-528. Aizenman, CD, Kirkwood, A., and Bear MF. (1996). Current source density analysis of evoked responses in visual cortex in vitro: Implications for the regulation of long-term potentiation. Cerebral Cortex 6, 751-758.
Kirkwood, A., Lee, H.-K. & M. F. Bear (1995). Long-term potentiation and experience-dependent plasticity in visual cortex are coregulated by age and experience. Nature 375: 328-331.