Sastry Bhagavatula


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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Effects of Sleep-deprivation on Long-term Depression of Excitatory Synaptic Transmission in the CA1 Region of the Hippocampus (2012)

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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Activity-mediated plasticity of GABA equilibrium potential in the CA1 region of the rat hippocampus (2011)

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system (CNS). GABAA receptor mediated inhibitory postsynaptic currents (IPSCs) can affect both excitatory and inhibitory synapses, and thus, regulate CNS network activity. Amplitudes and the direction of IPSCs are subject to changes in the GABA equilibrium potential (EGABA). Changes in EGABA can affect various types of activity-dependent plasticity of the IPSC. Interestingly, EGABA is set at a more positive level in neonatal than that in adult central neurons, rendering GABA excitatory in neonates and inhibitory in adults. Therefore, mechanisms underlying activity-mediated as well as age-dependent plasticity of EGABA in rat hippocampus were examined in the current study. Since EGABA is mainly determined by the levels of intracellular Cl⁻ concentration ([Cl⁻]i) in central neurons, the activities of two cation-Cl⁻ cotransporters (K⁺⁻Cl⁻ cotransporter, KCC2 and Na⁺⁻K⁺⁻Cl⁻ cotransporter, NKCC1) contribute to changes in EGABA. Accordingly, factors which influence KCC2 or NKCC1 activity can induce shifts in EGABA. In this thesis, the involvement of GABAB receptors, metabotropic glutamate receptors (mGluRs), G-proteins and postsynaptic Ca²⁺ in the regulation of KCC2 or NKCC1 activity, and thus in EGABA in immature and juvenile hippocampal CA1 neurons were examined. Whole-cell patch recordings were made from hippocampal CA1 pyramidal neurons (from 9-12 or 3-5 day old rats), in a slice preparation. Glutamatergic excitatory postsynaptic currents were blocked with dl-2-Amino-5-phosphonovaleric acid (APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). Western blot and immunohistochemistry methods were also used to monitor changes in receptor distribution and localization. The results indicate that shifts in EGABA are associated with several types of activity-mediated plasticity of IPSCs via changes in the activity of KCC2 or NKCC1 in hippocampal neurons. Interestingly, one type of specific, and behaviorally relavant, stimulation (theta burst stimulation, TBS) is able to induce a two-direction-shift in EGABA in juvenile and neonatal hippocampal neurons. GABAB receptors and G-porteins are involved in TBS-induced shifts in EGABA in juvenile hippocampal neurons while both postsynaptic Ca²⁺ and mGluRs appear to contribute to TBS-induced shifst in EGABA in both juvenile and neonatal neurons. However, the exact signal transduction pathways involving those above-mentioned factors awaits further investigation.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

The effects of sleep deprivation on 5-HT1A and 5-HT2A receptor expression in the hippocampus (2015)

No abstract available.


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