Bidirectional modulation of long-term synaptic depression by cyclic nucleotide -dependent protein kinases
Santschi, Linda Anita
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Dynamic changes in the weight of synaptic strengths studied in vitro may reproduce processes that underlie information storage in the brain, and those involved in the establishment of appropriate synaptic segregation during development of neural networks. Therefore, the elucidation of underlying mechanisms of activity-dependent synaptic plasticity should have great impact on our understanding of both normal and pathological brain function and development. In this thesis, I describe a newly-discovered experimental method for inducing a form of long-term synaptic depression (LTD) by chemical manipulation alone without induction of electrical activity. This chemically-induced LTD (CLTD) at Schaffer collateral-CA1 hippocampal synapses is dependent upon concomitant elevation of cyclic GMP and inhibition of the cyclic AMP-dependent protein kinase (PKA).;Data from intracellular sharp electrode recordings, where I applied pharmacologic agents selectively into the postsynaptic pyramidal neuron, support a presynaptic site of induction of CLTD. In an effort to confirm the locus of kinase action (or inaction in the case of PKA) as predominantly presynaptic, I utilized an independent method sensitive to the probability of transmitter release: namely, assessing changes in the paired-pulse facilitation (PPF) ratio, following the induction of both CLTD and stimulus-induced LTD. In a further examination of the presynaptic hypothesis, I investigated the effects of CLTD and associated PPF in another area of the hippocampus: the CA3 region. Single CA3 hippocampal pyramidal cells receive two anatomically distinct excitatory synaptic inputs: a commissural-associational (comm/assoc) input from ipsilateral and contralateral CA3 pyramidal neurons, and a mossy fiber (MF) input from dentate granule cells.;Since chemical LTD is critically dependent upon the inhibition of PKA, in my final experiments, I investigated the role of neurotransmitter receptors negatively coupled to adenylate cyclase (including class II and III metabotropic glutamate receptors, and, A1 adenosine receptors), which could potentially mediate the expression of CLTD. I have found that group II, but not group III, metabotropic receptors (mGluRs) and A1 adenosine receptors are critically involved in the induction of stimulus-induced LTD. In contrast, CLTD bypasses the need for activation of these receptors, presumably by correctly targeting the necessary presynaptic effectors through direct chemical manipulation.;Our ability for complex reasoning is the kind of higher-order cognitive ability which is thought to distinguish human beings from other organisms. Much of what shapes "who we are" depends intimately upon how we process experiential events and how we remember this information. (Abstract shortened by UMI.).