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Ted
Abel, Ph.D.
Professor,
Dept of Biology
319 Leidy Labs
(215) 898-5614 FAX: (215) 898-8780
email: abele@sas.upenn.edu
http://www.bio.upenn.edu/faculty/abel/
Click here for selected publications since Dr. Abel's arrival at Penn
RESEARCH INTERESTS
The molecular basis of synaptic plasticity, learning and memory; the molecular basis of sleep/wake regulationRESEARCH TECHNIQUES
Creation and analysis of genetically modified mice; behavioral assays of learning and memory; electrophysiological recordings from hippocampal neurons; EEG and EMG recording from awake miceRESEARCH SUMMARY
Synaptic plasticity, the change in the strength of neuronal connections in the brain, is thought to underlie memory storage and may play a crucial role in a variety of neurological and mental disorders, including mental retardation, Alzheimer's disease and depression. One goal of our research is to use transgenic mice to explore the molecular basis of synaptic plasticity and memory storage. Transgenic techniques can be used to express gene products designed to inhibit or enhance the activity of endogenous signaling pathways with a high degree of molecular specificity. The transgenic approach is spatially and temporally more restricted than the conventional gene knockout approach, thereby allowing for a more direct correlation between a behavioral deficit and synaptic physiology in the adult brain. Recently, we have extended our studies of genetically modified mice to examine the role of specific signal transduction pathways in sleep/wake regulation.The Molecular Basis of Long-Term Memory Storage
One form of synaptic plasticity that has received much attention is long-term potentiation (LTP), an activity-dependent form of synaptic enhancement. Like many forms of memory and synaptic plasticity, LTP in the hippocampus has distinct temporal phases. Long-lasting LTP (L-LTP) differs from the early phase of LTP in requiring protein kinase A (PKA) activity, protein synthesis and transcription. To explore the molecular basis and behavioral significance of long-lasting forms of synaptic plasticity, we have produced mice in which PKA activity in the hippocampus is reduced by the transgenic expression of R(AB), a dominant negative form of the regulatory subunit of PKA. R(AB) transgenic mice exhibit selective impairments in long-term contextual memory and long-lasting forms of hippocampal LTP. These long-term memory impairments are paralleled at the systems level by a long-term instability of place cells in R(AB) transgenic mice. We have also used these R(AB) transgenic mice to explore the molecular basis of the trial spacing effect at the electrophysiological and behavioral level. Spaced training is generally more effective than massed training for learning and memory, and our experiments suggest that enhanced memory following spaced training is particularly sensitive to protein synthesis and PKA inhibition.
The critical molecular targets of PKA and the identity of genes whose expression is regulated by this signal transduction pathway during memory storage remain crucial open questions, and R(AB) transgenic animals provide a physiological system in which to define the molecular events that are downstream from PKA activation. These biochemical and molecular studies will examine the PKA targets CREB and protein phosphatase inhibitor-1 and investigate the role of PKA in gene induction following learning. This induction of gene expression may be mediated by PKA and CREB as well as by the transcriptional coactivator and histone acetyltransferase CREB binding protein (CBP). To explore the spatial and temporal patterns of activation of the transcription factor CREB, we have constructed a novel chimeric transcription factor, tTA-CREB, which combines the DNA binding domain of a mammalianized and optimized tetracycline sensitive transactivator with the activation domains of CREB. By expressing this chimeric transcription factor in transgenic mice in combination with appropriate tetracycline-responsive reporter genes, we are attempting to monitor reporter gene induction repeatedly and non-invasively using molecular imaging approaches.
One of the challenges in the study of signal transduction pathways in neurons is to understand the way in which signals are restricted to subcellular compartments and how different signaling pathways interact. To explore these issues, we are investigating the role of A kinase anchoring proteins (AKAPs) in learning and synaptic plasticity. AKAPs localize PKA to specific subcellular locations and assemble PKA into signaling modules that include phosphodiesterases, phosphatases, ion channels and receptors. A truncated form of one AKAP, Ht31, has been used as an inhibitor capable of blocking the interactions between PKA and other AKAPs. To study the role of PKA localization via interactions with AKAPs in learning and memory, we have generated conditional transgenic mice expressing a truncated form of Ht31 in neurons within the forebrain using the CaMKIIa promoter and the tetracycline regulatory system. We are examining learning and memory as well as synaptic plasticity in these transgenic mice to characterize the role of A kinase anchoring in hippocampal and amygdala function.
Spatial and Temporal Regulation of Transgene Expression
Inducible systems are crucial for determining if the phenotype observed in adult animals is due to acute expression of the transgene or due to an indirect effect of the transgene on developmental processes. Such regulation may be achieved by combining regionally restricted promoters with the tetracycline-responsive system. We have developed new lines of transgenic mice in which expression of the R(AB) transgene is temporally, quantitatively and spatially regulated to define precisely the role that PKA plays in memory acquisition, consolidation, and retrieval. We are developing promoters that drive expression of transgenes in restricted regions of the brain, so that behavioral deficits may be assigned unambiguously to such defined brain structures as individual subfields within the hippocampus. In terms of synaptic plasticity, this approach will allow us to determine whether the transgene is acting pre- or postsynaptically. By using inducible systems to express transgenes that enhance the cAMP/PKA system, we are exploring whether long-term memory can be improved by increasing signaling through the PKA pathway. Because of the slow time course of the tetracycline-responsive system, we are exploring the use of mutated steroid hormone binding domains as well as the use of heterologous receptor systems to rapidly regulate the cAMP/PKA signal transduction pathway.Molecular Mechanisms of Extinction
Many molecular accounts of long-term memory storage postulate that the synthesis of new proteins is necessary for long-term changes in neuronal function. These experiments generally have examined the learning that occurs as associations are acquired between neutral and biologically important stimuli. Little is known about the importance of protein synthesis in the establishment of memories for extinction, which occurs as the relations established during acquisition are severed. We have found that although memories for the acquisition of spatial and contextual learning required protein synthesis, memories for extinction formed in the absence of protein synthesis. These results suggest that acquisition and extinction are mediated by distinct molecular mechanisms and that long-term memories can form in the absence of protein synthesis. An important question is to determine the molecular mechanisms that underlie the long-term behavioral changes that occur during extinction, and experiments are in progress to explore this question.
Mouse Models of Endophenotypes of Psychiatric Disorders
Recent evidence suggests that disturbances in intracellular signaling may contribute to schizophrenia. Studies in humans indicate that activity within the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway may be upregulated in the central nervous systems of schizophrenia patients. Schizophrenia patients exhibit several fundamental cognitive and neurobehavioral dysfunctions (endophenotypes) that can be objectively measured and quantified for the purposes of experimental analysis. Two such endophenotypes are inhibitory gating deficits and explicit learning impairments. These endophenotypes represent basic information processing disturbances that may contribute to the profound cognitive disturbances and thought disorders evident in schizophrenia. Because these endophenotypes can be readily modeled in laboratory animals, they serve as critical windows for elucidating the neurobiological basis for abnormal information processing in schizophrenia. We have found that transgenic mice overexpressing a constitutively active form of the signaling protein Gsa (Gsa*) in forebrain neurons exhibit deficits in animal models of inhibitory gating and explicit learning. We are currently investigating whether these deficits can be reversed by treatment with antipsychotics and whether antipsychotics can rescue the spatial learning deficits in these transgenics.
CREB and Sleep/Wake Regulation
Although much is known about the neural systems and neurotransmitters that regulate sleep and wakefulness, studies of the molecular regulation of sleep/wake states are only beginning to identify key molecules in intracellular signaling pathways that control these processes. The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. In rodents, levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB may play a role in sleep/wake regulation in mammals. Our studies of sleep/wake states in mice lacking the a and D isoforms of Creb demonstrate that CREB acts to promote wakefulness. Over a 24-hour period, wake was significantly decreased in CrebaD mutant mice by approximately 100 minutes, and time spent in non-rapid eye movement (NREM) sleep was correspondingly increased. This decrease in wakefulness was largely due to an inability of Creb mutant mice to maintain the longer periods of wakefulness that occur during the nocturnal active period. CrebaD mice had decreased levels of theta activity during wake and REM sleep, suggesting that CREB plays a critical role in cortical arousal. Our data, together with that from studies of Drosophila, indicate that there are molecular mechanisms that promote wakefulness, possibly driven by wake-active neurotransmitters, such as norepinephrine. Indeed, norepinephrine can function to activate CREB. We hypothesize that CREB activity is normally altered by state-related changes in neural function; in turn, a suite of genes is activated by CREB and these genes subserve the functions of waking. We are identifying the targets of CREB important for sleep/wake regulation by analyzing knockout mice lacking the CREB target genes such as bdnf or zif268 and by carrying out gene expression studies.
KEY WORDS:
Memory storage; synaptic plasticity; long-term potentiation; behavior; genetically modified mice, sleep-wake regulation
