RicardoDolmetschRicardo Dolmetsch, PhD
Cambridge, Massachusetts, United States

Our group is interested in understanding the underlying pathophysiological basis of schizophrenia and autism by taking advantage of human genetics. One important area of research is the role of copy number variants (CNVs) in the pathophysiology of psychiatric and neurodevelopmental diseases. Recent studies have identified a wide variety of CNVs that confer susceptibility to psychiatric disease. 22q11 deletion syndrome (DS) is the most common genetic cause of schizophrenia and autism, but the mechanisms by which this mutation leads to disease are not understood. 22q11 DS is characterized by a 1.5 or 3 MB heterozygous deletion that results in the loss of 25 or 39 genes, respectively. We have generated induced pluripotent stem cells (iPSCs) from patients with 22q11 DS and have identified defects in gene expression and signaling in neurons derived from these cells. These defects may explain the susceptibility of 22q11 DS patients to schizophrenia. The goal of this research is to delete single genes and sets of genes in human iPSCs to determine which genes are responsible for the cellular phenotypes in these cells. Ultimately this study will help us understand the underlying molecular basis of disease in patients with 22q11 DS and may help us identify new targets for drug development in schizophrenia and autism. 

In chronic neurodegenerative disorders, there are common pathological features underlying progressive neuronal degeneration. These include accumulation of abnormal protein aggregates, glial activation, and pro-inflammatory cytokine release, which amplify neurotoxic effects in affected brains. A second research area (with co-mentors Rajeev Sivasankaran and Taeho Kim) focuses on understanding cellular and molecular mechanisms that drive these processes. We are particularly interested in identifying core mechanisms that drive pathogenesis of frontotemporal dementia (FTD), the second most common form of pre-senile dementia which primarily affects the frontal and temporal lobes of the brain – the areas generally associated with personality, behavior, language, and motor functions. We have established robust cellular assays to monitor neuronal and microglial dysfunction in FTD. Furthermore, using innovative proteomic technology, we have identified unique approaches to interrogate signaling pathways implicated in neuronal survival and neuroinflammatory processes. Our current aim is to validate and investigate pathways that go awry in pathological conditions, with the ultimate goal of developing disease-modifying therapies for FTD and related neurodegenerative disorders.

Selected Publications

Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.
Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J, Dolen G, Bader PL, Grueter BA, Goold C, Fisher E, Clifford K, Rengarajan P, Kalikhman D, Loureiro D, Saw NL, Zhengqui Z, Miller MA, Lerch JP, Henkelman RM, Shamloo M, Malenka RC, Crawley JN, Dolmetsch RE.
Cell Rep. 2014 May 22;7(4):1077-92.

SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.
Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE. Nature. 2013 Nov 14;503(7475):267-71. 

Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.
Krey JF, Paşca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, Dolmetsch RE.
Nat Neurosci. 2013 Feb;16(2):201-9.

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