Several cellular factors--with profoundly different spatial and temporal properties--contribute to the ability of dendrites to integrate and shape synaptic responses in neurons. The primary goal of this project will be to investigate how Ca2+ release from intracellular stores in hippocampal CA1 and CA3 pyramidal neurons contributes to dendritic function. To accomplish this goal we will use whole-cell patch-clamp recording and high-speed fluorescence imaging in slices from adult (>6 weeks old) mice and rats. The underlying theme is that internal Ca2+ release, and consequent propagation of intracellular Ca2+ waves, is not only capable of contributing to synaptic plasticity such that occurs with long-term potentiation (LTP) and long-term depression (LTD), but also provides a temporally unique and biochemically robust means for communication within individual neurons. In addition to investigating internal Ca2+ release, we propose to examine whether Ca2+ release modulates ion-gated and ligand-gated channels, and how this modulation affects dendritic function and synaptic integration. More specifically, our first aim will be to continue studies characterizing the basic properties of synaptically evoked internal Ca2+ release in hippocampal neurons under physiologically realistic conditions. We will also test the hypothesis that kainate receptor-activation can lead to internal Ca2+ release via metabotropic receptor activation. In the second aim we will investigate the hypothesis that an increase in InsP3 at hippocampal mossy fiber synapses, and consequent internal Ca2+ release, is capable of inducing long-term changes in synaptic strength such that occurs with LTP and LTD. In the third aim we will examine whether internal Ca2+ release and Ca2+ waves can modulate backpropagating action potentials and ligand-gated channels, and if so, determine how this modulation contributes to dendritic function and synaptic integration, particularly as it relates to modifying input from convergent subsets of synapses on pyramidal neurons. More generally, the results of these experiments will provide essential information concerning the functional properties of hippocampal pyramidal neurons, and will also clarify at a more global level the cellular mechanisms underlying information processing by single neurons in the hippocampus.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Asanuma, Chiiko
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Yale University
Schools of Medicine
New Haven
United States
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El-Hassar, Lynda; Simen, Arthur A; Duque, Alvaro et al. (2014) Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels. Biol Psychiatry 76:476-85
El-Hassar, Lynda; Hagenston, Anna M; D'Angelo, Lisa Bertetto et al. (2011) Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca²? wave-dependent activation of SK and TRPC channels. J Physiol 589:3211-29
Sears, Robert M; Liu, Rong-Jian; Narayanan, Nandakumar S et al. (2010) Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone. J Neurosci 30:8263-73
Hagenston, Anna M; Rudnick, Noam D; Boone, Christine E et al. (2009) 2-Aminoethoxydiphenyl-borate (2-APB) increases excitability in pyramidal neurons. Cell Calcium 45:310-7
Fitzpatrick, John S; Hagenston, Anna M; Hertle, Daniel N et al. (2009) Inositol-1,4,5-trisphosphate receptor-mediated Ca2+ waves in pyramidal neuron dendrites propagate through hot spots and cold spots. J Physiol 587:1439-59
Tecuapetla, Fatuel; Koós, Tibor; Tepper, James M et al. (2009) Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals. J Neurosci 29:8977-90
Hagenston, Anna M; Fitzpatrick, John S; Yeckel, Mark F (2008) MGluR-mediated calcium waves that invade the soma regulate firing in layer V medial prefrontal cortical pyramidal neurons. Cereb Cortex 18:407-23
Brennan, Avis R; Dolinsky, Beth; Vu, Mai-Anh T et al. (2008) Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory. Learn Mem 15:93-6
Gipson, Keith E; Yeckel, Mark F (2007) Coincident glutamatergic and cholinergic inputs transiently depress glutamate release at rat schaffer collateral synapses. J Neurophysiol 97:4108-19
Hertle, D N; Yeckel, M F (2007) Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus. Neuroscience 150:625-38

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