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Examples of UAB IDDRC Research by Project Leaders

Rosalinda Roberts
The Roberts laboratory studies the synaptic organization of postmortem striatum in schizophrenic subjects (SZ) at the ultrastructural level. Previous results indicated an increase in cortico-striatal type synapses in the caudate matrix and putamen patches that were not caused by antipsychotic medication. The higher density of cortical-type synapses in the SZ cases than in controls suggests hyper-stimulation of striatal projection neurons. This could have several important and different downstream effects depending on the precise circuitry involved. The current studies seek to identify the specific striatal circuitry affected in SZ 1) To test the hypothesis that limbic and prefrontal circuitry are perturbed at the level of the striatum; 2) To examine synaptic density of striatonigral and striatopallidal neurons in the patch and matrix in select striatal territories; 3) To test the hypothesis that striatopallidal matrix neurons in the caudate receive more excitatory inputs; 4) To test the hypothesis that typical vs atypical antipsychotic drugs have different effects on the patch and matrix compartment; and 5) To determine if the morphological alterations seen will show regional variations that are consistent with the differential effects of typical and atypical APDs on the activity of midbrain DA neurons, particularly with respect to tyrosine hydroxylase+ neurons. The proposed experiments will: 1) distinguish between drug effects and disease related alterations in synaptic pathology; 2) will provide insight into the mechanisms of action of antipsychotic drugs; and 3) are an important initial step in identifying putative abnormal striatal circuitry that may underlie some of the psychopathology of schizophrenia.

J. David Sweatt
Dr. Sweatt’s laboratory focuses on the role of signal transduction mechanisms in long-term potentiation (LTP) and memory formation, critical factors in hippocampal synaptic plasticity and learning. These studies were initiated about 10 years ago in hippocampal slices and have transitioned to studies in the behaving animal and discovered that extracellular signal-regulated kinase (ERK) is activated in the hippocampus with contextual associative conditioning and that ERK activation is necessary for fear conditioning and for spatial learning in the Morris water maze. Studies from a wide variety of laboratories have now shown that MAPK signaling is involved in many forms of synaptic plasticity and learning, in essentially every species that has so far been examined. Given the clear importance of understanding the roles and regulation of ERK in synaptic plasticity and learning, the Sweatt laboratory will pursue studies related to the hypotheses of a role for the scaffolding protein Kinase Suppressor of Ras (KSR) in hippocampal ERK activation, LTP, and hippocampus-dependent memory, that Histone Acetyl Transferases (HATs) are a target of ERK regulation in the hippocampus, and that the dual-specificity MAPK phosphatase MKP-3 is a negative feedback regulator of ERK. These studies will give us insights into key functional loci in the hippocampal ERK MAP Kinase cascade, a new signal transduction pathway involved in transcriptional regulation, synaptic plasticity, and memory formation.

Edward Taub
Edward Taub is a behavioral neuroscientist who developed a new family of techniques, termed Constraint-Induced Movement therapy or CI therapy, which has been shown to be effective in improving the rehabilitation of movement after brain injury. This work is derived from basic research he carried out with deafferented monkeys whose upper extremities had been surgically deprived of sensation. CI Therapy consists of a family of therapies; their common element is that they teach the brain to functionally "rewire" itself (most likely through mechanisms that involve changes in synaptic function after training periods) following a major injury such as stroke traumatic brain injury or in certain forms of developmental disorders such as the hemiplegic form of cerebral palsy. This is based upon research carried out by Dr. Taub, and collaborators showing that patients can "learn" to improve the motor ability of the more-affected parts of their bodies and thus cease to rely exclusively or primarily on the less-affected parts. These therapies have significantly improved quality of movement and substantially increased the amount of use of a more-affected extremity in the activities of daily living for a large number of patients.

Scott Wilson
The identification of genes involved in neurodegeneration is a powerful means to understand the mechanisms of neuronal cell loss. Dr. Wilson identifies these genes through a variety of approaches in mice that include transgenics, gene-knockouts and positional cloning. He has recently cloned the mouse neurological mutation ataxia. The ataxia mouse displays a severe tremor and hind limb paralysis by 5 weeks of age. He showed that ataxia gene encodes Usp14, a member of the ubiquitin/proteosome pathway. During our analysis of the ataxia mouse, we found that loss of Usp14 results in synaptic transmission defects in both the central and peripheral nervous system. Since the members of this pathway act on a variety of substrates, we believe that the identification of the substrate(s) for Usp14 will provide important insights into the pathogenesis of the ataxia tremor and paralysis. In addition to Usp14, we are also investigating the function of several other members of the ubiquitin/proteosome pathway that are involved in neuronal function. The mouse waltzer mutation is another mutation that he recently cloned. The waltzer gene encodes Cdh23, the newest member of the cadherin superfamily. Loss of this gene product in humans results in both auditory and vestibular dysfunction. We are currently producing antibodies and generating other alleles of Cdh23 to understand how this gene product functions in the perception of sound and maintenance of balance. In addition to these projects, he is also in the process of identifying other spontaneous neurological mutations in mice, taking a candidate gene approach to identify the mutated genes in other neurological mice.

David Bedwell
The Bedwell laboratory is examining the effect of the ability of aminoglycosides and other pharmacological agents have the ability to suppress stop mutations in the mucopolysaccharidosis MPS I-H related to deficiency of the lysosomal enzyme, iduronidase. Previous studies in this laboratory showed that the aminoglycoside gentamicin can suppress the IDUA Q70X and W402X premature stop mutations (carried by ~70% of MPS I-H patients) and restore enough a-L-iduronidase activity to normalize glycosaminoglycan levels in cultured primary fibroblasts derived from an MPS I-H patient [Keeling et al., Human Molecular Genetics 10: 291-299 (2001)]. To explore this novel therapeutic treatment further, we recently succeeded in constructing an /c/tya-W402X knock-in mouse in which the /DLW-W402X premature stop mutation found in MPS I-H patients was introduced into the corresponding position in the mouse Idua gene. This new mouse model will allow us to test the hypothesis that the suppression of premature stop mutations and/or nonsense-mediated mRNA decay (NMD) can restore enough a-L-iduronidase activity to correct the disease manifestations of MPS I-H in vivo.

Etty (Tika) Benveniste
The Benveniste laboratory is studying the inflammatory events in the central nervous system (CNS) related to Multiple Sclerosis (MS), Alzheimer disease (AD), and Spinal Cord Injury (SCI). Activated macrophages/microglia are central to this response due to production of a wide array of cytokines, chemokines, matrix metalloproteinases and neurotoxins, and ultimately to glial/neuronal injury and death. We hypothesize that aberrant CD40 expression by macrophages/microglia, induced by cytokines such as IFN-gamma and TNF-alpha, contributes to inflammatory responses in the CNS. We also propose that strategies to suppress CD40 expression will attenuate inflammation and neuronal damage within the CNS, which will ultimately be of benefit in MS, AD and SCI. The mediators that regulate expression of CD40 in macrophages/microglia (both induction and inhibition) function at the level of gene transcription, thus it is imperative that we gain a better understanding of the molecular mechanisms involved in these responses. We will elucidate the contribution of the TNF-alpha signaling pathway and subsequent NF-kappaB activation to IFN-gamma induced CD40 gene expression in macrophages/microglia and determine the interactions between STAT-1alpha and NF-kappaB transcription factors and the CD40 promoter, and between transcription factors and various co-transactivators including CBP, p300 and CARM1, to understand CD40 gene expression. They will also determine the molecular mechanism(s) underlying suppression of CD40 expression in these cells. Our proposed studies will provide a comprehensive assessment of CD40 production and function in macrophages/microglia, thereby setting the foundation for future therapeutic manipulation of this critical immunoregulatory protein.

Mark Bevensee
The Bevensee laboratory is interested in the cellular and molecular physiology of intracellular pH (pHi) regulation and acid-base transport in tissues such as brain and heart. Changes in cell and/or tissue pH can influence important processes such as enzyme activity and neuronal firing. To regulate pHi, cells have evolved mechanisms such as membrane transporters to move acids (e.g., H+) or bases (e.g., bicarbonate or HCO3) across their plasma membranes. Some of these proteins include Na-H exchangers, Na/HCO3 cotransporters, and Na-dependent and -independent Cl-HCO3 exchangers. Much is unknown about the function, regulation, and molecular identities of these and other acid-base transport mechanisms. In our cellular studies, we use fluorescence imaging and patch-clamp techniques to identify and characterize the function of pHi-regulating mechanisms in mammalian neurons and glia. Studies include evaluating ion dependencies, inhibitors, and pH- and voltage-dependencies of transport proteins. Dr. Bevensee is also interested in the effects of neuromodulators and cell-volume perturbations on pHi regulation and the correlation between pH1 changes and neuronal firing. In another area of research, the laboratory is elucidating the molecular nature of Na/HCO3 cotransporters (NBCs) and other members of the bicarbonate-transporter superfamily. Many NBC-related proteins are present in brain and heart. The laboratory is identifying the cDNAs that encode bicarbonate transporters, and subsequently characterizing the structure-function relationships and regulation of the proteins expressed in either frog oocytes impaled with microelectrodes, or transfected mammalian cells loaded with ion-sensitive dyes. The combined results from cellular and molecular studies will enhance our understanding of both the physiology of pHi regulation and the biophysics of bicarbonate transport.