UBC Theses and Dissertations
Effects of sleep-deprivation on long-term depression of excitatory synaptic transmission in the ca1 region of the hippocampus Tadavarty, Ramakrishna
In the central nervous system (CNS), synapses are considered to be the loci for memories. Activity dependent strengthening or weakening of synaptic strength via long-term potentiation (LTP) or depression (LTD), respectively, is widely postulated to underlie memory formation. Sleep, which is universally present across most species in the animal kingdom, aids learning and formation of memories. On the contrary, sleep-deprivation (short- or long- term), disrupts memory formation and task re-performance. Exactly how this happens is unclear. In the present study, we hypothesized that sleep-deprivation affects LTD, which may in-turn be responsible for cognitive deficits observed at the behavioral level. Following a 12 h period of sleep-deprivation, LTD of the population excitatory postsynaptic potentials (pEPSPs) induced using a 20 Hz, 30s tetanus to Schaffer collaterals in the CA1 region of the hippocampus, is enhanced in sleep-deprived (SD) rats. We investigated the role of metabotropic glutamate receptors (mGluRs), γ-Aminobutyric acid (GABA)-A receptors (GABAA-Rs), GABAB-Rs and N-methyl-D-aspartic acid receptors (NMDARs) in the LTD. The requirement of Ca²⁺ through L- and T- type voltage-gated calcium channels (VGCCs) and intracellular stores was also studied. Results indicate that mGluRs, a release of Ca²⁺ from intracellular stores and GABAB-Rs are required for LTD. Studies with mGluR antagonists suggest that while mGlu1Rs are involved in both short-term depression and LTD, mGlu5Rs participate mostly in LTD. CGP-55845, a GABAB-R antagonist, partially suppressed LTD in normally sleeping (NS) rats, while completely blocking in SD rats. Moreover, GS-39783, a positive allosteric modulator for GABAB-Rs, suppressed the pEPSP in SD, but not NS, rats. Since both mGluRs and GABAB-Rs seem to be involved in the LTD, especially in SD rats, changes in receptor expression pattern and/or dimerization were examined using immunohistochemical, co-localization and co-immunoprecipitation (co-IP) techniques. Sleep-deprivation induced an increase in GABAB-R1 and mGlu1αR expression in the CA1 region of the hippocampus. In addition, co-localization and heterodimerization between mGlu1αR/GABAB-R1 and mGlu1αR/GABAB-R2 is enhanced in SD rats. Taken together, our findings present a novel form of LTD sensitive to the activation of mGluRs and GABAB-Rs, and reveal, for the first time, that sleep-deprivation induces alterations in the expression and dimerization of these receptors.
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