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Examples of UAB IDDRC Research by Project Leaders

Robin Lester
The Lester laboratory studies the pivotal role of CNS nicotinic acetylcholine receptors (nAChRs) in tobacco addiction has focused our attentions on understanding the overall function of these receptors in the brain both under physiological and diseased conditions. nAChRs are ligand-gated ion channels composed of five individual protein subunits that cause neuronal excitation when bound and activated by synaptically released neurotransmitter, acetylcholine, or exogenous drugs like nicotine. Molecular biological studies have characterized at least ten receptor subunits that can be assembled together in numerous combinations giving rise to a wide variety of nAChRs with distinct functional roles. It is because of this diversity that nAChRs have been implicated in a range of CNS behaviors from pain sensation to learning and memory, and multiple pathological states such as epilepsy and schizophrenia. High-resolution electrophysiological (patch-clamp) techniques combined with intracellular Ca2+ measurements provide the most powerful way of examining these receptors. The physiological and pharmacological properties of single and multiple nAChR channels in isolated membrane patches and whole cells can be fully resolved using these methods. The roles of nAChRs at both pre and postsynaptic zones of central synapses can be studied by recording from visually identified neurons in brain slice preparations. The electrophysiology is complemented by molecular biological approaches that allow the expression and characterization of known cloned nAChRs and the determination of nAChR RNAs from CNS neurons (by single cell RT-PCR).

Guillermo Marqués
Developmental and adult synaptic plasticity, regulation of gene expression during nervous system development, cell signaling and signal transduction by the TGF-ß/BMP pathway in neurons represent targets of projects in the laboratory centered on the role of TGFß growth factors in developmental and activity-induced synaptic plasticity. The goal of Dr. Marques laboratory is understanding molecularly how the post-synaptic cell regulates the efficiency of synaptic transmission, resulting in synapse potentiation or depression and the appropriate behavioral correlate. A combination of genetic, molecular and biochemical approaches are used to this end, and although the favored experimental model is the Drosophila larva neuromuscular junction, other organisms and experimental paradigms are currently being considered.

Lori McMahon
The McMahon laboratory studies the role of inhibitory interneurons and inhibitory mechanisms in governing the activity of local synaptic circuits. A major effort is aimed at understanding the role of the inhibitory amino acids, glycine and taurine, and glycine-gated chloride channels in providing neuronal inhibition in hippocampus, a brain region highly susceptible to seizure activity and excitotoxic cell death. Our experiments are directed at determining whether enhancing glycine channel activity with receptor agonists and modulators depress seizure activity and prevent or minimize excitotoxic cell death. Another major focus is directed toward elucidating the cellular and molecular mechanisms that underlie long-term changes in the strength of excitatory synaptic transmission and how these mechanisms are altered in neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease. A novel form of long-term depression (LTD) is being evaluated in hippocampus that is induced via activation of the M1 subtype of muscarinic cholinergic receptors. Also, the effects of estrogen on synaptic function and plasticity are being evaluated to determine how estrogen-induced changes in synaptic plasticity contribute to the memory enhancing effects of this hormone.

James Meador-Woodruff
This project is designed to examine the expression of glutamate receptors and related interacting proteins in the thalamus from patients with schizophrenia and a comparison group. The glutamate hypothesis of schizophrenia is supported by pharmacological evidence suggesting involvement of the NMDA receptor, and we have previously demonstrated changes in NMDA receptor stoichiometry in thalamus in this illness. The postsynaptic NMDA receptor complex also includes glutamate receptor interacting proteins that are critical for normal receptor assembly, trafficking, insertion in the plasma membrane, and activation. In addition, colocalization and stimulus specific activation of AMPA receptors are required for initiation of long term potentiation and other NMDA receptor-mediated correlates of neuroplasticity. Thus, we hypothesize that there are abnormalities in the expression of the NMDA and/or AMPA receptors, as well as abnormalities of glutamate receptor interacting proteins associated with the postsynaptic receptor signaling complex in the thalamus in schizophrenia. Accordingly, we will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. We propose to conduct a detailed examination of functionally linked molecules in the postsynaptic receptor complex, by measuring transcript and protein levels expressed in functionally distinct thalamic nuclei. Further, we will perform cell level studies that will permit comparisons of changes in mRNA expression by intrinsic GABAergic neurons and glutamatergic relay neurons. Examination of the expression of these molecules critical for neurotransmission in the thalamic glutamate synapse will highlight abnormalities that can be more profitably targeted for the generation of novel treatment modalities for this disabling illness.

Vladimir Parpura
Astrocytes, a subtype of glial cell, exhibit a form of excitability based on intracellular Ca2+ variations. These intracellular calcium variations, i.e., oscillations can be evoked by neurotransmitters. The goal of this research is to test the hypotheses that glutamate release from astrocytes is controlled by the frequency of calcium oscillations and that PKA and PKC modulate calcium-dependent glutamate release from astrocytes. This study will provide new and important information on how astrocytes communicate with neurons. Since astrocytes modulate synaptic transmission by releasing glutamate, this new insight into glial action has potential to change the way we think about central nervous system functions and dysfunctions.

Lucas Pozzo-Miller
The goal of this research is to characterize the functional role of structurally defined neuronal compartments such as spines, dendrites, and presynaptic terminals, and how they participate in synaptic function and plasticity. The work focuses on the transient elevations of intracellular free Ca2+ concentration induced by neuronal activity, and defining their role in synaptic plasticity investigating the effects of neurotrophins on synapses as an initial approach to characterize the regulation of synaptic transmission and plasticity by slow-acting, non-classical neuromodulators. The lab studies the effects of brain-derived neurotrophic factor (BDNF) on dendritic Ca2+ signaling in hippocampal neurons from normal rats, as well as from BDNF or TrkB receptor knockout mice. The modulation of Ca2+ signals in spines and dendrites may underlie the actions of neurotrophic factors in hippocampal synaptic transmission and plasticity. A related project is to characterize the effect of neurotrophic factors on the structural differentiation of dendrites, spines and synapses.

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