RECENT PREDOCTORAL TRAINEES
Alana Conti (Neuroscience)
THE ROLE OF CREB IN STRESS AND ANTIDEPRESSANT RESPONSES
Thesis Advisor: Julie A. Blendy, Ph.D.
My thesis project examines the role of CRE-binding transcription factors
in adaptive effects to stress produced by antidepressant drugs. Behavioral,
neuroendocrine and molecular responses are studied in CREB and CREM mutant
mice. While the CREB mutant mice continue to demonstrate behavioral responses
when given antidepressant drugs, downstream expression of a CREB target
gene, BDNF, is abolished in these mice compared to controls. Conversely,
while CREM mutant mice do not display alterations in the behavioral responses
to antidepressant treatment, the ability of antidepressants to suppress
stress-induced release of the stress hormone, corticosterone is prevented
in these mice. My final experiments measure endocrine-related gene expression
in control and CREM mutant mice to elucidate the genes responsible for
antidepressant-induced corticosterone release.
Keith Fournier (Pharmacology)
TRAFFICKING OF A NEURONAL GLUTAMATE TRANSPORTER
Thesis Advisor: Michael B. Robinson, Ph.D.
I am studying the intracellular protein machinery responsible for regulating
the cell surface trafficking and function of the neuronal glutamate transporter
EAAC1. Studies are investigating how activation of protein kinase C (PKC)
ultimately up-regulates the function and cell surface levels of EAAC1
using molecular and genetic techniques to manipulate the endo and exocytotic
machinery of cell systems. Studies have established that PKC is unlikely
to act by modifying protein stability. PKC is likely re-distributing EAAC1
from a sub-cellular compartment to the plasma membrane. Using cultured
neurons, endogenous levels of EAAC1 were shown to be reduced by application
of botulinum toxin C1 in solution, indicating that the cell's exocytotic
machinery (the SNARE proteins) regulate EAAC1 cell-surface expression.
James Crowley (Pharmacology)
GENETIC REGULATION OF THE EFFECTS OF SSRIs
Thesis Supervisor: Irwin Lucki, Ph.D.
My project will identify genomic differences between inbred mouse strains
responsible for differential sensitivity to the behavioral effects of
SSRIs (selective serotonin reuptake inhibitors). A survey of 8 inbred
mouse strains for sensitivity to the SSRI citalopram in the tail suspension
test indicated substantial differences between strains in baseline behavior
and sensitivity to citalopram. The pattern of strain differences parallels
previous strain survey findings by our lab using the forced swim test
and the SSRI fluoxetine. Current experiments include: 1) establishing
the behavioral and pharmacological specificity of identified stain differences,
and 2) breeding studies aimed at identifying quantitative trait loci (QTL)
underlying strain differences in SSRI sensitivity.
Conor McDonough (Neuroscience)
CELLULAR COMPARTMENTALIZATION OF CYCLIC AMP AND FUNCTION
Thesis Advisor: Edwin G. Abel, Ph.D.
Cyclic AMP-dependent protein kinase (PKA) is critical for the establishment
of long term memory and lasting changes in synaptic efficacy. PKA is often
compartmentalized within various subcellular by interactions with A-kinase
anchoring proteins (AKAP), and its function is directly impacted by this
anchoring. Using genetically modified mice in electrophysiological, imaging
and biochemical studies, I am working to elucidate the role of AKAP-PKA
interactions in synaptic plasticity.
Elisa A. Waxman (Pharmacology)
REGULATION OF SYNAPTIC PROTEINS BY NMDA-R2 RECEPTORS
Thesis Advisor: David Lynch, M.D., Ph.D.
The N-methyl-D-aspartate receptor (NMDA-R) has been implicated in several
psychiatric diseases. In disorders such as schizophrenia, atypical neuroleptics
can inhibit the NMDA-R and create an antipsychotic effect. The relationship
between the NMDA-R and psychiatric diseases has not yet been defined.
Gene regulation produced by the NMDA-R through p38 mitogen-activated protein
kinase (MAPK) is a potential area of involvement. We are exploring the
involvement of NMDA-R2-subtype activation of p38 MAPK in regard to the
development of scaffolding proteins, and other signaling proteins, at
the synapse that modify neurotransmission.
RECENT POSTDOCTORAL TRAINEES
Christos Ballas, M.D., Ph.D.
GENES INVOLVED IN AFFECTIVE ILLNESS
Preceptor: Wade Berrettini, M.D., Ph.D.
I am currently examining candidate genes that mediate the genetic susceptibility
to bipolar disorder and/or schizophrenia. A novel intronless gene found
within intron 5 of the Golf gene, 22444, was initially found to be in
linkage disequilibrium in a sample of schziophrenia patients. Two other
candidate genes, CHMP1 (procollagen endopeptidase) and MPPE1 (metallophosphoesterase)
are also currently being investigated. SNPs, first in exons and then later
in introns, are also being examined to determine whether any, or some,
of these polymoprhisms are associated with psychiatric disease states.
Jason Glanzer, Ph.D.
MOLECULAR MARKERS IN PSYCHIATRIC ILLNESS
Preceptor: James Eberwine, Ph.D.
The laboratory uses new subtraction hybridization protocols that have
been developed to easily permit the clon-ing of mRNA molecules from localized
brain regions and the development of cDNA libraries from single neuronal
cells. These libraries are then used to identify molecular markers of
CNS dysfunction in brain autopsy samples from psychiatric and neurological
patients. Using single-cell preparations of cells, I determined optimal
conditions for growth and plating of astrocytes and learned several strategies
for imaging flouresence in GFP-transfected astrocytes. Finally, I was
trained in DNA array methods with several opportunities for troubleshooting.
Jessica Holden, Ph.D.
SIGNAL TRANSDUCTION AND ANXIETY BEHAVIOR IN MOUSE MODELS
Preceptor: Julie Blendy, Ph.D.
My research in the Blendy laboratory focuses on the roles of CREM and
CREB in anxiety disorders. Studies indicate that these transcription factors
play a role in depression, and given the clinical comorbidity of depression
and anxiety, it is reasonable to hypothesize a role for these proteins
in anxiety disorders as well. The goals of my research are to identify
potential differences in basal levels of anxiety in wild type, CREM deficient,
and CREB deficient mice using a battery of tests. Studies will then determine
if CREB and/or CREM are required for the action of different types of
Brian Hoshaw, Ph.D.
NEUROGENESIS AND ANTIDEPRESSANT DRUGS
Preceptor: Irwin Lucki, Ph.D.
I am currently examing the role of neurotrophins and neurogenesis in antidepressant
activity. Chronic administration of antidepressant drugs increases levels
of neurotrophins that could contribute to increased neurogenesis. The
effects of central administration of the neurotrophic factors brain derived
neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) are
being examined for their ability to increase neurogenesis and to alter
behaviors related to depression, anxiety and cognition. The neural mechanisms
underlying the effects of neurotrophic factors could be targets for the
development of novel psychiatric medications.
Mike Kaplan, Ph.D.
MOLECULAR REGULATION OF SYNAPTIC PLASTICITY
Preceptor: Edwin G. Abel, Ph.D.
I am working on the molecular mechanisms of long-term potentiation by
studying genetic manipulations of relevant biochemical pathways using
two lines of transgenic mice. The first line lacks the protein inhibitor-1,
which has been proposed to act as a "gate" that allows long term plasticity
to be expressed by PKA-dependent suppression of phosphatases. We are examining
potential deficits in neural function using long-term potentiation as
a test of the "gate" hypothesis. The second line expresses an inhibitory
form of CREB called ICER and have displayed some behavioral deficits.
I will examined them for alterations in neural processing related to learning
and memory by using long-term potentiation.
Michelle D. Jones, Ph.D.
SEX DIFFERENCES IN AFFECTIVE BEHAVIORS
Preceptor: Irwin Lucki, Ph.D.
I am examining sex differences regulated by serotonin in the 5-HT1B receptor
knockout mice as a model for gender-related vulnerability to stress-related
psychiatric disorders. Mice with genetic deletion of 5-HT1B receptors
show consistently altered stress-induced response that is both gender
and genotype specific. Female mutants, but not male mutants, demonstrate
higher levels of basal extracellular serotonin release. Using the tail
suspension test (TST) and forced swim test (FST) as animal models of stress-induced
depressive behavior, female 5-HT1B receptor knockout mice were significantly
less immobile than their wild-type counterparts due to higher levels of
5-HT. In contrast, male mutant mice demonstrated immobility times comparable
to wild-type animals of both genders. Additional behavioral paradigms
will study sex-selective changes in anxiety and learning. Identification
of the hormonal contributors to gender-related differences in neurotransmitter
release and behavior will provide an important model of gender-related
vulnerability to psychiatric disorders.