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5109E Neuroscience Research Building
(919) 966-0025 office
(919) 966-0031 lab
(919) 966-6927 fax
bphilpot@med.unc.edu |
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Center
& Program Memberships: |
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Lab
Members
Adam
Roberts
Postdoctoral Fellow
Koji
Yashiro
Graduate Student
Rebekah
Corlew
Graduate Student
Maile
Henson
Graduate Student
Jacquie
de Marchena
Graduate Student
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Ben Philpot, PhD
Assistant Professor
Education:
BS, Duke
University, 1992
PhD, University of Virginia, 1997
Modification
of the Cerebral Cortex by Sensory Experience
Our memories
are formed through experiences that leave an indelible trace in the
brain.
Scientists have appreciated that sensory experience is not only necessary
for the formation of memories, but sensory experience is also required
for the proper development of the brain. During a critical period of development,
experience-evoked neural activity refines synaptic connections so that
appropriate connections are strengthened and maintained while inappropriate
connections are weakened and eventually eliminated. In this manner, sensory
experience
helps transform an immature neural network into one that extracts meaningful
information from the environment. We aim to characterize how experience
shapes synaptic plasticity during development such that stable and appropriate
synaptic connections are formed.
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1: Visual experience in wild-type (wt)
mice alters the properties of synaptic plasticity. A) Low-magnification
view of a visual cortex slice preparation. Field potentials are
recorded with a glass micropipette in layers 3 and evoked by layer
4 stimulation. B) Changes in synaptic strength can by measured by
the amplitude of the field potential before and after high-frequency
stimulation. This figure demonstrates that 40 Hz stimulation increases
synaptic strength more in visual cortex of dark-reared (DR) mice
than light-reared controls (LR). |
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We have taken advantage of the visual cortex to examine properties of experience-dependent
synaptic plasticity. Visual cortex is amenable to these studies because
1) the visual environment is easily modified, 2) sensory manipulations have
clear consequences on the receptive field properties of neurons, 3) the
intracortical organization of primary visual cortex is well-defined, 4)
the cortex is a primary site for receptive field plasticity, and 5) sensory
experience or deprivation have dramatic behavioral consequences (i.e. sight
or blindness). A well-known outcome of monocular deprivation is that visually
driven inputs are strengthened and maintained in the visual cortex while
synaptic connections that do not contribute to postsynaptic firing are weakened.
The strengthening and weakening of synapses have been termed long-term potentiation
(LTP) and long-term depression (LTD), respectively, and are thought to be
a natural consequence of patterned neural activity. |
The current focus of our laboratory is to examine how experience modifies
the properties of synaptic plasticity (LTP and LTD) so that the visual
world can be properly analyzed. To address this question, we employ techniques
such as electrophysiology to examine how visual experience shapes synaptic
function. We also take advantage of genetically engineered mice to test
specific hypotheses of synaptic plasticity. We aim to fully characterize
experience-dependent modifications in excitatory synaptic transmission
in layers 2/3, the initial site for receptive field plasticity. Because
activation of the NMDA-type glutamate
receptor (NMDAR) is required for receptive field plasticity and the induction
of LTP/LTD, we hypothesize that changes in NMDAR function might regulate
the properties of synaptic plasticity. Included among the questions our
lab is addressing are: 1) How does experience modify the different types
of synaptic inputs that converge onto cortical layer 2/3 neurons? 2) How
does visual experience modify NMDAR function? 3) How do changes in NMDAR
composition alter synaptic transmission and plasticity? 4) By what mechanism
does visual experience regulate the properties of synaptic plasticity?
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Figure
2: Visual experience alters NMDA receptor
currents. A) Example of a whole-cell recording made from a visualized
layer 3 pyramidal cell. B) NMDA receptor currents are longer in cells
from dark-reared cortex as compared to light-reared controls. |
These studies
will characterize how experience regulates the elementary properties of
plasticity and excitatory synaptic transmission. We hope to unlock mechanisms
for restoring synaptic plasticity in visual cortex that had been rendered
dysfunctional due to amblyopia. Moreover, it is our hope that heuristics
learned in the visual cortex might be generally applicable to synaptic
plasticity associated with development, drug addiction, and/or learning
and memory.
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Figure
3: Immunoblot demonstrating protein levels of NR2A, NR1, GluR1,
and synaptophysin (Syn) in wild-type (+/+), heterozygote (+/-), and
NR2A knockout (-/-) mice. The NR2A NMDA receptor subunit is absent
in NR2A knockout mice, while NR1 NMDA receptor subunit and the GluR1
AMPA receptor subunit levels remain unchanged. Levels of the synaptic
protein, synaptophysin, are used for normalization purposes. |
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Figure
4: A layer 3 pyramidal cell filled with a fluorescent marker. |
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Recent
Publications:
Corlew R, Wang Y, Ghermazien H, Erisir A, Philpot BD. (2007) Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J Neurosci. 2007 Sep 12;27(37):9835-45.
Philpot BD, Cho KK, Bear MF. (2007) Obligatory Role of NR2A for Metaplasticity in Visual Cortex. Neuron 53:495-502.
Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD. (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. Journal of Neuroscience 27:11354-65.
Yashiro K, Corlew R, Philpot BD. (2005) Visual deprivation modifies both presynaptic glutamate release and the composition of peri-/extrasynaptic NMDA receptors in adult visual cortex. Journal of Neuroscience 25:11684-11692.
Philpot
BD, Espinosa JS, Bear MF. (2003) Evidence for altered NMDA receptor function
as a basis for metaplasticity in visual cortex. J
Neurosci 23:5583-5588.
Sawtell NB,
Frenkel MY, Philpot BD, Nakazawa K, Tonegawa S, Bear MF.
(2003) NMDA receptor-dependent ocular dominance plasticity in adult visual
cortex. Neuron 38(6):977-985.
Philpot BD, Bear MF. (2002) Synaptic plasticity in an altered state. Neuron 33: 665-667.
Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, Tonegawa S. (2001) Forebrain-specific calcineurin
knockout selectively impairs bidirectional synaptic plasticity and working
memory. Cell 107:617-629.
Snyder EM, Philpot BD, Huber KM, Dong X, Fallon JR, Bear
MF. (2001) Internalization of ionotropic glutamate receptors in response
to metabotropic glutamate receptor activation. Nat
Neurosci 4:1079-1085.
Philpot BD, Sekhar AK, Shouval HZ, Bear MF. (2001) Visual
experience and deprivation bidirectionally modify the composition and
function of NMDA receptors in visual cortex. Neuron 29:157-169.
Philpot BD, Weisberg MP, Ramos MS, Sawtell NB, Tang Y-P,
Tsien JZ, Bear MF. (2001) Effect of transgenic overexpression of NR2B
on NMDA receptor function and synaptic plasticity in visual cortex. Neuropharmacology 41:762-770.
*Quinlan EM, *Philpot BD, Huganir RL, Bear MF. (1999) Rapid,
experience-dependent expression of synaptic NMDA receptors in visual cortex
in vivo. Nat
Neurosci 2:352-357.
*These authors contributed equally to this work.
Philpot BD, Lim JH, Halpain SH, Brunjes PC. (1997) Experience-dependent
modifications in MAP2 phosphorylation in rat olfactory bulb. J
Neurosci 17:9596-9604.
Philpot BD, Lim JH, Brunjes PC. (1997) Activity-dependent
regulation of calcium-binding proteins in the developing rat olfactory
bulb. J
Comp Neuro 387:12-26.
postdoctoral position, postdoc, NMDA receptor,
NR2B, NR2A, metaplasticity, synaptic plasticity, BCM theory, amblyopia,
LTP, LTD, sliding threshold, STDP, glutamate receptor, IR-DIC, in vitro
electrophysiology, whole-cell recording, field potential, spike-timing
dependent plasticity |
