PostDoc Position in the Mano Lab, City College, New York City: Novel strategies for glutamate clearance in a glia- deprived synaptic hub: Lessons from C. elegans
We study normal and pathological signaling by
the neurotransmitter glutamate. The job opening is to study the
physiology of functional neuronal circiut isolation and glutamate transporters. In addition
to
standard C. elegans methods (such as genetics, cell and molecular
biology) we will study transporter function using electrophysiology in Xenopus
oocytes expressing nematode cRNA, and by imaging neuronal activity in intact
worms using Ca2+-sensitive GFP and microfluidic chips.
Our lab is at the department of Physiology,
Pharmacology,
& Neuroscience, the CUNY School of Medicine at City College, the
City
University of New York (CUNY). Our campus is growing, with the recent
addition of two new science buildings: the Advanced Science Research
Center (ASRC, a facility that hosts top research groups from the CUNY
system and includes a new
Neuroscience center), and the City College Neuroscience Cluster at the
new Center for Discovery & Innovation (CDI) building (where our lab
is located). City College is located
in western Harlem in uptown Manhattan, in close proximity to many
leading academic institutes,
placing us at the heart of an exciting and collaborative academic
atmosphere, a hub of neuroscience research,
and vibrant city life. Good housing options are available close to
campus, and
we are in commuting distance from suburban areas in NY, NJ, and CT.
If you are a motivated, multitasking neurophysiologist interested
in exploring new approaches in molecular neuroscience and genetics, this
project will be an excellent fit for you. Applicant should have a PhD in a relevant
field of biology and a record of excellence in neurophysiology. Please e-mail a brief cover letter
describing your research experience, CV, and contact information for 2-3
references to: imano@ccny.cuny.edu
Project Abstract Novel strategies for glutamate clearance in a glia- deprived synaptic hub: Lessons from C. elegans
The
widespread use of Glutamate (Glu) as the major excitatory
neurotransmitter (NT) in the mammalian brain is both critical for
normal physiology and a source of predicaments: a) As seen in stroke
and a range of neurodegenerative diseases, any disruption in Glu
clearance causes its accumulation, leading to over- excitation of
postsynaptic cells and excitotoxic neurodegeneration. b) The use of the
same NT in so many adjacent synapses can cause signaling to “bleed
over” between neuronal circuits, and the loss of processing fidelity.
An idealized view of the brain describes synapses as well insulated
from each other, enveloped by glia that expresses high levels of Glu
clearing transporters (GluTs). However, a more realistic examination
reveals that some particularly-important brain areas (e.g.,
hippocampus) show severely deficient glial isolation, with estimated
2/3 of released Glu seeping out of the original synapse. How sufficient
Glu clearance is achieved in glia-deficient brain areas remains
unclear. To overcome the limitation of current techniques we will study
Glu clearance in the glia-deficient synaptic hub of the C. elegans
nerve ring. We are aided by the availability of information on the
precise identification of individual neurons, the exact location of
their synapses, the circuits that they participate in, and the sensory
inputs and behavioral outputs of these circuits. Together with animal
transparency and the wide availability of optogenetic tools, this is an
ideal system to study Glu clearance without perturbing interstitial
fluids. In our recent studies we have discovered that specific synapses
fall into watershed territories of Glu clearance, and that synapses
might be affected by the agitation of body fluids. We therefore propose
a novel concept, where Glu clearance in a glia-deficient synaptic hub
can be robust enough to allow functional synaptic isolation. Such
robust clearance depends on division of labor between proximal and
distal GluTs, and is facilitated by agitation and perfusion of
interstitial fluids. To provide further support to this model we will
use genetically-encoded florescent Ca2+ reporters (GCaMP) to follow
synaptic activity and assign additional synapses and circuits to GluT
drainage territories; we will stimulate one circuit and record
responses from an adjacent one to detect spillover; we will use
genetically-encoded fluorescent detectors to study the flow of Glu in
the interstitial space; we will study the effect of paralysis on
neuronal responses and Glu flow; We will correlated the differences
between the structure of proximal and distal GluTs to potential
differences transport in affinity and capacity. These studies will
provide novel insights to mechanisms of robust Glu clearance in the
absence of glia, and highlight the significance of agitation of
interstitial fluids in synaptic areas that are deficient in glia
insulation, a feature shared between nematodes and some areas of the
mammalian brain. These insights will aid in the design of future
therapeutic interventions to prevent excitotoxicity (seen in stroke and
a range of neurodegenerative diseases), and highlight the significance
of vascular pulsatility in CNS physiology. Supported by NIH grant # 1R21NS098350-01
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