The 100 billion neurons in the human brain have an average of 10,000 synapses. By establishing a dynamic network of synaptic connections, the brain is able to attain the level of functional complexity that underlies human behavior. The efficiency of signal transmission at synapses is constantly being adapted in response to experience as encoded by neural activity. This synaptic plasticity is critical for the fine- tuning of brain development as well as higher brain function such as learning and memory. The plasticity of synapses is modulated and maintained by processes that are sensitive to neuronal activity and cell-cell contact. Trans-synaptic protein interactions induce differentiation of the synapse and regulate the morphology and function of synapses. Release of neurotransmitter regulates the activity of the neuron and activates a variety of second messenger pathways including calcium-signaling systems, which have a central role in regulating both rapid synaptic plasticity and long-term changes in synaptic connections through the activation of gene transcription. These activity-regulated genes then modulate the function of the neuron and can directly affect synapse function. The proposed Conte Center will investigate the inter- and intracellular signaling to and from the synapse that induce synapse formation and differentiation and regulate synaptic efficacy. These signal transduction pathways are initiated at sites of neuronal cell contact by extracellular signals and are then relayed to the nucleus and finally cycle back to the synapse to regulate synaptic function. The proposed Center brings together six leading laboratories in the study of synaptic function to take multiple interdisciplinary collaborative approaches to investigate the molecular mechanisms involved in regulating synaptic transmission and plasticity. Richard Huganir will be identifying molecules involved in the formation, differentiation and regulation of excitatory synapses in the brain. Paul Worley and Sol Snyder will be analyzing how macromolecular signaling complexes at excitatory synapses control neuronal calcium signaling and synaptic function. David Linden and David Ginty will be analyzing how calcium regulates neuronal transcription factors and gene expression. Dwight Bergles will be studying the interaction of glutamate transporters and metabotropic glutamate receptors and the role of this interaction in regulating synaptic function. All of these projects center on the synapse and address how extracellular and intracellular signals converge on the synapse to sculpt its morphology and function. Many neurological and psychiatric diseases result from defects in the development and/or function of synapses. Thus, understanding the mechanisms regulating the formation and modulation of synaptic transmission in the brain is critical for the development of treatments for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH084020-05
Application #
8306547
Study Section
Special Emphasis Panel (ZMH1-ERB-A (01))
Program Officer
Asanuma, Chiiko
Project Start
2008-09-24
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,775,856
Indirect Cost
$693,017
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Paukert, Martin; Agarwal, Amit; Cha, Jaepyeong et al. (2014) Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82:1263-70
Mihalas, Anca B; Araki, Yoichi; Huganir, Richard L et al. (2013) Opposing action of nuclear factor *B and Polo-like kinases determines a homeostatic end point for excitatory synaptic adaptation. J Neurosci 33:16490-501
Kim, Yu Shin; Kang, Eunchai; Makino, Yuichi et al. (2013) Characterizing the conductance underlying depolarization-induced slow current in cerebellar Purkinje cells. J Neurophysiol 109:1174-81
Zeiler, Steven R; Gibson, Ellen M; Hoesch, Robert E et al. (2013) Medial premotor cortex shows a reduction in inhibitory markers and mediates recovery in a mouse model of focal stroke. Stroke 44:483-9
Sia, G M; Clem, R L; Huganir, R L (2013) The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342:987-91
Park, Joo Min; Hu, Jia-Hua; Milshteyn, Aleksandr et al. (2013) A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization. Cell 154:637-50
Linden, David J (2012) A late phase of LTD in cultured cerebellar Purkinje cells requires persistent dynamin-mediated endocytosis. J Neurophysiol 107:448-54
Benediktsson, Adrienne M; Marrs, Glen S; Tu, Jian Cheng et al. (2012) Neuronal activity regulates glutamate transporter dynamics in developing astrocytes. Glia 60:175-88
Holmseth, Silvia; Dehnes, Yvette; Huang, Yanhua H et al. (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32:6000-13
De Biase, Lindsay M; Kang, Shin H; Baxi, Emily G et al. (2011) NMDA receptor signaling in oligodendrocyte progenitors is not required for oligodendrogenesis and myelination. J Neurosci 31:12650-62

Showing the most recent 10 out of 19 publications