Assistant Professor, Department of Comparative Biosciences
Ph.D. Northwestern University
Altered synaptic plasticity in the etiology of neuropsychiatric disorders
Dendritic spines are the sites of most excitatory connections in the central nervous system. The central goal of my laboratory is to delineate the molecular and biochemical mechanisms that regulate dendritic spine plasticity in both the normal and diseased brain. In particular, using animal models, I am interested in recapitulating the genetic and biochemical alterations identified in neuropsychiatric disorders to identify brain region-specific aberrations in dendritic spine formation, stability, and experience-dependent remodeling. I then aim to understand how these regional synaptic changes, in turn, contribute to specific disease-associated behavioral phenotypes. Finally, I am interested in understanding how environmental-based risk factors for neuropsychiatric disease interact with specific genetic susceptibility factors to produce synaptic and behavioral phenotypes.
One approach used by my lab is in vivo viral-mediated gene transfer in which the expression of a gene and associated protein product are manipulated in an individual brain region. Further, within individual brain regions, viral-mediated gene transfer can enable the genetic manipulation of specific neuronal subtypes and specific neuronal populations. Viral approaches have the advantage of directly linking the altered expression/activity of neuropsychiatric disease-associated proteins in a single brain region with specific behavioral endophenotypes. This helps clarify the role of altered dendritic spine morphogenesis in individual brain structures in mediating disease-associated behavioral dysfunction.
While the study of individual brain regions helps demystify the critical structures regulating specific behaviors, complex behaviors are invariably the product of dynamic regulations in the functional connectivity between multiple brain regions. Altered structural and functional connections between brain regions, both proximal and distal, are commonly associated with neuropsychiatric disorders. However, the consequences of these alterations on neuronal structure and behavior are seldom known. Using in vivo circuit-based manipulations (e.g., optogenetics and DREADDs), my laboratory aims to understand how altered interbrain region connectivity patterns identified in neuropsychiatric diseases impact dendritic spine formation, maturation, and stability, and the consequent effects on behavioral functioning.
Using the approaches described above, my laboratory seeks to understand the etiology of executive processing (e.g., working memory) dysfunction in schizophrenia by the investigation of specific prefrontal cortical circuits, as well as understand how altered structural and functional plasticity in brain reward circuits potentially give rise to the social cognitive and social motivational impairments characteristic of autism spectrum disorders.
Please see pubmed for a full list of publications
Cahill ME, Walker DM, Gancarz AM, Wang ZJ, Lardner CK, Bagot RC, Neve RL, Dietz DM, Nestler EJ. The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor (SRF) signaling. Molecular Psychiatry (2017) (in press)
Ceglia I, Lee KW, Cahill ME, Graves SM, Dietz D, Surmeier DJ, Nestler EJ, Nairn AC, Greengard P, Kim Y. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proceedings of the National Academy of the Sciences (2017) 114 (6): 1395-1400
Cahill ME, Bagot RC, Gancarz AM, Walker DM, Sun H, Wang Z, Heller EA, Feng J, Kennedy PJ, Koo JW, Cates HM, Neve RL, Shen L, Dietz DM, Nestler EJ. Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling. Neuron (2016) 89: 566-582
Sun H, Damez-Werno DM, Scobie KN, Shao N, Dias C, Rabkin J, Koo JW, Korb E, Bagot RC, Ahn FH, Cahill ME, Labonté B, Mouzon E, Heller EA, Cate H, Golden SA, Gleason K, Russo SJ, Andrews S, Neve R, Kennedy PJ, Maze I, Dietz DM, Allis CD, Turecki G, Varga-Weisz P, Tamminga C, Shen L, Nestler EJ. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nature Medicine (2015) 21: 1146-1153.
Russell TA, Blizinsky KD, Cobia DJ, Cahill ME, Xie Z, Sweet RA, Duan J, Gejman PV, Wang L, Csernansky JG, Penzes P. A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness. Nature Communications (2014) 5: 4858
Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, Fallon B, Mazei-Robison M, Ku SM, Harrigan E, Winstanley CA, Joshi T, Feng J, Berton O, Nestler EJ. Prefrontal Cortical Circuit for Depression- and Anxiety-Related Behaviors Mediated by Cholecystokinin: Role of ΔFosB. Journal of Neuroscience (2014) 34: 3878-3887.
Wang X, Cahill ME, Werner CT, Christoffel DJ, Golden SA, Xie Z, Loweth JA, Marinelli M, Russo SJ, Penzes P, Wolf ME. Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization. Journal of Neuroscience (2013) 33: 11012-11022
Cahill ME, Reemers C, Jones KA, Xie Z, Sweet RA, Penzes P. Neuregulin1 signaling promotes dendritic spine growth through kalirin. Journal of Neurochemistry (2013) 126: 625-635.
Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, Cahill ME, Dias C, Ribeiro E, Ables JL, Kennedy PJ, Robison AJ, Gonzalez-Maeso J, Neve RL, Turecki G, Ghose S, Tamminga CA, Russo SJ. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nature Medicine (2013) 19: 337-344.
Dietz DM, Sun H, Lobo MK, Cahill ME, Chadwick B, Gao V, Koo JW, Mazei-Robison MS, Dias C, Maze I, Damez-Werno D, Dietz KC, Scobie KN, Ferguson D, Christoffel D, Ohnishi Y, Hodes GE, Zheng Y, Neve RL, Hahn KM, Russo SJ, Nestler EJ. Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons. Nature Neuroscience (2012) 15: 891-896.
Deo AJ, Cahill ME, Li S, Goldszer I, Henteleff R., VanLeeuwen JE, Rafalovich I, Gao R, Stachowski EK, Sampson AR, Lewis DA, Penzes P, Sweet RA. Increased expression of kalirin-9 in the auditory cortex of schizophrenia subjects: its role in dendritic pathology. Neurobiology of Disease (2012) 45: 796-803.
Cahill ME, Jones KA, Rafalovich I, Xie Z, Barros CS, Müller U, Penzes P. Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. Molecular Psychiatry (2012) 17: 99-107.
Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nature Neuroscience (2011) 14: 285-293.
Xie Z, Cahill ME, Radulovic J, Wang J, Campbell SL, Miller CA, Sweatt JD, Penzes P. Hippocampal phenotypes in kalirin-deficient mice. Molecular and Cellular Neuroscience (2011) 46: 45-54.
Xie Z, Cahill ME, Penzes P. Kalirin loss results in cortical morphological alterations. Molecular and Cellular Neuroscience (2009) 43: 81-89.
Cahill ME, Xie Z, Day M, Barbolina MV, Photowala H, Miller CA, Weiss C, Radulovic J, Sweatt JD, Disterhoft JF, Surmeier DJ, Penzes P. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proceedings of the National Academy of the Sciences (2009) 106: 13058-13063.
Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME, Xie Z, Jones KA, Quilliam LA, Prakriya M, Penzes P. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nature Neuroscience (2009) 12: 1275-1284.
Xie Z, Srivastava DP, Photowala H, Kai L, Cahill ME, Woolfrey KM, Shum CY, Surmeier DJ, Penzes P. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron (2007) 56: 640-656.