Why do autistic neurons learn differently?

$251
Raised of $2,000 Goal
13%
Ended on 7/20/13
Campaign Ended
  • $251
    pledged
  • 13%
    funded
  • Finished
    on 7/20/13

About This Project

Neurons! single molecules!

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What is the context of this research?

The human brain is composed of billions of neurons which communicate with each other through electrical and chemical connections. The basis of learning and memory is thought to arise from long term changes in the strengths of these connections, called synapses, a process known as synaptic plasticity. Since the discovery of synaptic plasticity much work has gone into elucidating the molecular mechanisms that allow for changes in synaptic strength, and in particular how these mechanisms go awry in neurological disease.

Autism Spectrum Disorders (ASD) are a group of common developmental neurological disorders that affect ~ 1 in 88 individuals. Shared symptoms include difficulty in socializing and communication as well as repetitive behaviors. Using mouse models of ASD researchers have uncovered abnormalities in the ways neurons communicate with each other that likely underlie the pathology of ASD.

Our laboratories use mouse models of ASD to investigate how neuronal activity is altered in the disease. We believe that changes in the ability of neurons to undergo synaptic plasticity may result in the cognitive symptoms observed in ASD patients. We record neuronal activity from acute slices of mouse hippocampus, a brain region known to be important in learning and memory. We also visualize changes in the structure of ASD synapses using light microscopy and immunohistochemical techniques. Through an understanding of the molecular neuropathophysiology of ASD we hope to design treatments that can be used to ameliorate the symptoms of ASD patients and restore proper cognitive function.

What is the significance of this project?

The prevalence of ASD has risen dramatically in the past decade. While many resources have been put towards the task of understanding these common disorders there is still much work to be done. Ongoing clinical trials for drugs designed to treat ASD are promising however, these drugs will only be effective for certain types of ASD. We believe that basic scientific research is required to instruct future clinical therapies.

I am a MD/PhD student at the Albert Einstein College of Medicine in the laboratories of Dr. Pablo Castillo and Dr. Bryen Jordan. Our laboratories are well equipped to conduct basic research into the neuropathology of mouse models of ASD. My mentors Dr. Castillo and Dr. Jordan have long track records of scientific excellence in the field of neuroscience. Our publication record can be viewed at the research repository of the National Institutes of Health (www.pubmed.gov: Klein ME; Castillo PE; Jordan BA)

What are the goals of the project?

I am currently funded by a training grant from the National Institutes of Health (NIH). My research is also supported by grants awarded to my mentors Dr. Castillo and Dr. Jordan. Unfortunately, the recent sequestration will likely result in across the board cuts to existing and future NIH grants. Because of this I am exploring alternative funding opportunities including putting my project on Microryza. The funds pledged here will be used to purchase research supplies including pharmacological reagents for use in examining neuronal activity and antibodies for immunohistochemistry. A portion of the funds will also be used to pay open access fees to ensure that this research will be made publicly available.

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The experiments for this project involve the recording of electrical activity generated by neurons in mouse models of ASD. During these experiments we use pharmacology to induce synaptic plasticity in acutely dissected brains from ASD mouse models. We will also test the ability of these compounds to rescue synaptic deficits.

Other experiments will involve looking at the structure of ASD synapses at high resolution. We use fluorescent antibodies against components of the synapse to determine their presence with light microscopy.

The funds pledged for this project will be used to purchase these reagents including pharmacological agents and antibodies. A portion of the funds will also be used to pay open access fees to ensure that this research will be made publicly available.

Meet the Team

Matthew Klein
Matthew Klein
MD/PhD Student

Affiliates

BA, Biology, May 2005, Reed College
Masters of Science and Biomedical Research, September 2011
MD/PhD (student), August 2008 - present, Albert Einstein College of Medicine

Publications and Abstracts:

Klein ME, Younts TJ, Castillo PE, Jordan BA. The RNA binding protein Sam68 controls hippocampal synapse number and dendritic beta actin mRNA metabolism. PNAS. 2013 Feb 19; 110(8);3125-30.

Kessels HW, Kopec CD, Klein ME, Malinow R. Roles of stargazin and phosphorylation in the control of AMPA receptor subcellular distribution . Nat Neurosci. 2009 Jul;12(7):888-96. Epub 2009 Jun 21.

Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci. 2007 Dec;10(12):1513-4. Epub 2007 Nov 11.

Ehrlich I, Klein M, Rumpel S, Roberto Malinow. PSD-95 is required for activity-driven synapse stabilization. PNAS. 2007 Mar 6;104(10):4176-81. Epub 2007 Feb 27.

Vo N *, Klein ME *, Varlamova O, Keller DM, Yamamoto T, Goodman RH, Impey S. A cAMP response element binding protein-induced microRNA regulates neuronal morphogenesis. PNAS, 2005 Nov 8; 102(45):16426-31. Epub 2005 Oct 31.

Klein ME, Impey S, Goodman RH. Role reversal: the regulation of neuronal gene expression by microRNAs. Curr Opin Neurobiol. 2005 Oct;15(5):507-13.

Saito T, Guan F, Papolos DF, Lau S, Klein M, Fann CS, Lachman HM. Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-liked bipolar disorder. Mol. Psychiatry. 2001 Jul;6(4):387-95.

*These authors contributed equally
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Team Bio

I am interested in the study of the brain at the molecular and cellular level, specifically regulation of translation in neuronal processes. Dysfunction of local translation can lead to deficits in synaptic transmission, which in turn contribute to the pathophysiology of mental diseases. Through an understanding of the specific molecular mechanisms underlying synaptic dysfunction in mental diseases we will be able to design treatments for these disorders. I use a variety of techniques in the disciplines of molecular biology, and electrophysiology to consider the entirety of this problem. As a physician scientist I hope to help my patients with the present standard of care while researching the cures of the future.

Matthew Klein

I am interested in the study of the brain at the molecular and cellular level, specifically regulation of translation in neuronal processes. Dysfunction of local translation can lead to deficits in synaptic transmission, which in turn contribute to the pathophysiology of mental diseases. Through an understanding of the specific molecular mechanisms underlying synaptic dysfunction in mental diseases we will be able to design treatments for these disorders. I use a variety of techniques in the disciplines of molecular biology, and electrophysiology to consider the entirety of this problem. As a physician scientist I hope to help my patients with the present standard of care while researching the cures of the future.

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