Long term potentiation (LTP) is a widely used model in studies on molecular and cellular mechanisms underlying synaptic plasticity. Elucidating the molecular and cellular properties underlying LTP is the unifying objective of this proposal. Previous studies have determined a postsynaptic site for LTP induction. However, the cellular residence for LTP expression, whether pre- and/or postsynaptic, remains heavily debated. A postsynaptic site of induction and a presynaptic site of expression have generated much interest in retrograde messengers that would communicate the induction of LTP from the post- to presynaptic neuron. Moreover, to preserve the synapse specificity of LTP many believe that there must be an activity dependent interaction of retrograde messengers with presynaptic terminals. We have begun to test these hypotheses by developing an induction protocol using glutamate iontophoresis that reliably induces LTP in hippocampal slices in the absence of presynaptic transmitter release, evoked stimulation and action potentials. Our results place constraints on the involvement of activity dependent presynaptic mechanisms and retrograde messengers in LTP induction and expression. Namely, these processes must function in the absence of many forms of presynaptic activity. LTP induced by glutamate iontophoresis (""""""""ionto-LTP"""""""") will be used to elucidate pre- and postsynaptic mechanisms responsible for the induction and expression of LTP. We also propose experiments to test the involvement of retrograde messengers in ionto-LTP. LTP induction is dependent on Ca2+ activated protein kinases, however, the temporal duration of kinase activity required for LTP induction is unclear and controversial. Previous studies have simply assumed that the molecular mechanisms underlying LTP fall into two temporal stages, induction (seconds) and expression (hours). Our results indicate that there is critical window of protein kinase activity that occurs 2-10 min after the induction event. We believe this period of protein kinase activity is a stabilization or consolidation stage that occurs after induction, but is required for LTP expression. We plan to determine the temporal requirement for protein kinase activity during LTP consolidation, and to identify which specific protein kinase(s) is/are important during this period. The elucidation of the temporal requirement for kinase dependent processes will be instrumental to future studies on molecular changes responsible for LTP expression. Our preliminary results also indicate a role for protein kinases in regulating short-term synaptic plasticity and experiments are proposed to test kinase involvement in paired-pulse facilitation and post-tetanic potentiation. These studies are a multidisciplinary approach to elucidating mechanisms in plasticity and should provide new and important information about the role of second messenger-dependent events responsible for LTP expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032470-02
Application #
2270698
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1994-01-01
Project End
1997-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Kelly, Paul T; Mackinnon 2nd, Roger L; Dietz, Roger V et al. (2005) Postsynaptic IP3 receptor-mediated Ca2+ release modulates synaptic transmission in hippocampal neurons. Brain Res Mol Brain Res 135:232-48
Maher, Brady J; Mackinnon 2nd, Roger L; Bai, Jihong et al. (2005) Activation of postsynaptic Ca(2+) stores modulates glutamate receptor cycling in hippocampal neurons. J Neurophysiol 93:178-88
Wang, J H; Kelly, P (2001) Calcium-calmodulin signalling pathway up-regulates glutamatergic synaptic function in non-pyramidal, fast spiking rat hippocampal CA1 neurons. J Physiol 533:407-22
Ko, G Y; Kelly, P T (1999) Nitric oxide acts as a postsynaptic signaling molecule in calcium/calmodulin-induced synaptic potentiation in hippocampal CA1 pyramidal neurons. J Neurosci 19:6784-94
Wang, J H; Kelly, P T (1997) Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. J Neurosci 17:4600-11
Wang, J H; Kelly, P T (1997) Attenuation of paired-pulse facilitation associated with synaptic potentiation mediated by postsynaptic mechanisms. J Neurophysiol 78:2707-16
Wang, J H; Kelly, P T (1996) The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. Learn Mem 3:170-81
Wang, J H; Kelly, P T (1996) Regulation of synaptic facilitation by postsynaptic Ca2+/CaM pathways in hippocampal CA1 neurons. J Neurophysiol 76:276-86
Huber, K M; Mauk, M D; Kelly, P T (1995) LTP induced by activation of voltage-dependent Ca2+ channels requires protein kinase activity. Neuroreport 6:1281-4
Huber, K M; Mauk, M D; Thompson, C et al. (1995) A critical period of protein kinase activity after tetanic stimulation is required for the induction of long-term potentiation. Learn Mem 2:81-100

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