Title: The abrupt transition from theta to hyper-excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex
1The abrupt transition from theta to
hyper-excitable spiking activity in stellate
cells from layer II of the medial entorhinal
cortex
- Horacio G. Rotstein
- Department of Mathematical Sciences
- New Jersey Institute of Technology
- Network Synchronization From dynamical systems
to neuroscience - Leiden (NL) - May 27, 2008
2Collaborators
- Tilman Kispersky
- Program in Neuroscience - Boston University
- Nancy Kopell
- Math Center for BioDynamics Boston
University - Martin Wechselberger
- Math University of Sidney
- John White
- Biomedical Engineering University of Utah
3Entorhinal Cortex Hippocampus
- Photomicrograph of a section through the rat
hippocampal region (Gluck Myers). Adapted from
Amaral Witter (1989). - Photomicrograph of a section through the
rat hippocampal region (Gluck Myers). Adapted
from Amaral Witter (1989)
4Stellate cells (SCs)
- Entorhinal cortex (EC) is the interface between
the neocortex and the hippocampus. - Information flows from the neocortex
- to the hippocampus through the
- superficial layers (II and III) of the EC.
-
- SCs are the most abundant cell type
- in layer II of the EC.
- SCs are putative grid cells.
5Subthreshold oscillations (STOs)
- SCs develop rhythmic STOs at theta frequencies (8
12 Hz). - Spikes occur at the peaks of STOs but not at
every cycle. - Interaction between two currents h- and
persistent sodium. - Single cell phenomenon
- Depolarization increases from 1 to 3 (Adapted
from Dickson et al., J. Neurophysiol., 2000)
6SCs Theta regime (background)
- SCs have intrinsic biophysical properties that
endow them with the ability to display rhythmic
activity in the theta frequency regime (8 12
Hz) - Subthreshold oscillations (STOs) interaction
between a persistent sodium and a
hyperpolarization-activated (h-) current. - Spikes
- Mixed-mode oscillations (MMOs) STOs interspersed
with spikes - R., Oppermann, White, Kopell (JCNS 2005)
- R., Wechselberger, Kopell (Submitted)
- Focus issue on MMOs (Chaos 2008)
7SCs Hyperexcitable regime (this project)
- SCs have intrinsic biophysical properties that
endow them with the ability to display spiking
activity in the gamma frequency regime (60
Hz). - This time scale can be uncovered by phasic
excitation. - The frequency regime depends on a combination of
intrinsic and network properties. - Kispersky, White R. ,
Work in Progress.
8SC dynamic structure
- Nonlinearities and multiple time-scales in the
subthreshold regime - How are they created?
- How do they depend on the intrinsic SC
biophysical properties? - How do they interact with synaptic (excitatory
and inhibitory) inputs?
9SC biophysical model
10SC biophysical model
11SC biophysical model
12Subthreshold oscillations (STOs) and spikes in
the SC model
13STOs generated by persistent sodium channel
noise in the SC model
14Subthreshold Regime Reduction of Dimensions
- Multiscale analysis
- Identification of the active and inactive
currents - Identification of the appropriate time scales
15Subthreshold Regime Reduction of Dimensions
- Multiscale analysis
- Identification of the active and inactive
currents - Identification of the appropriate time scales
16Subthreshold regime reduced SC model
SC biophysical model
Subthreshold regime
17Subthreshold regime reduced SC model
18Subthreshold regime reduced SC model
19Subthreshold regime reduced SC model
SC biophysical model
Subthreshold regime
20Subthreshold regime reduced SC model
21Nonlinear Artificially Spiking (NAS) SC model
22Nonlinear Artificially Spiking (NAS) SC model
23Nonlinear Artificially Spiking (NAS) SC model
24Inhibitory inputs can advance the next spike by
killing an STO.
25Transition from theta to hyper-excitable (gamma)
rhythmic activity
- Experimental (in vitro) results
- There exist recurrent connections among SCs.
- These connections are similar in normal
(control) and epileptic cells. - Recurrent inhibitory circuits are reduced in
epileptic cells as compared to normal (control)
ones. - Recurrent circuits in layer II of MEC in a
model of temporal lobe epilepsy. Kumar,
Buckmaster, Huguenard, J. Neurosci. (2007)
26Minimal S-I network model
27Minimal S-I network model
- A minimal S-S network reproduces the
experimentally found transition form normal
activity to hyper-excitability in SCs due to lack
of inhibition
28Minimal S-I network model
- A minimal SIS network reproduces the
experimentally found transition form normal
activity to hyper-excitability in SCs due to lack
of inhibition
29Minimal SC network model (no inhibition)
- A small increase in the SC recurrent synaptic
conductance causes an explosion of the SC firing
frequency
30Minimal SC network model (no inhibition)
- A small increase in the SC recurrent synaptic
conductance causes an explosion of the SC firing
frequency
31Minimal S-I network model
- A small increase in the inhibitory input to the
SCs brings their frequency back to the theta
regime
32Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation - Single SC model representing a population of
synchronized (in phase) SCs.
33Single SC autapse (no inhibition)
- Effects of changes in the maximal conductances
34Single SC autapse (no inhibition)
- Effects of changes in the maximal conductances
35Single SC (no autapse - no inhibition)
36Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
37Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
38Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
39Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
40Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
41Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
42Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
43Single SC (no autapse - no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
44Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
45Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
46Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
47Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
48Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
49Single SC autapse (no inhibition)
- The abrupt changes in the SC firing frequency are
the result of phasic (synaptic) and not tonic
excitation
50Dynamic clamp experiments
- Single SC autapse (no inhibition)
- Tilman Kispersky John White
51Dynamic clamp experiments
-
- Voltage record of a stellate cell coupled to
itself. - Inset close up view of a single burst
- Under control conditions
52Dynamic clamp experiments
-
-
- Voltage record of a stellate cell coupled to
itself. - Inset close up view of a single burst
- Under linopiridine application (M-channel
blocker)
53Dynamic clamp experiments
- Freq. vs. current under control conditions
54Dynamic clamp experiments
55Minimal S-I network model
56Summary
- SCs have intrinsic biophysical properties that
endow them with the ability to display rhythmic
activity in the theta and gamma frequency
regimes (nonlinearities and time scale
separation) - In normal conditions SCs display theta rhythmic
activity (STOs and MMOs. - Abrupt transitions resulting from recurrent
excitation. - Theoretical predictions confirmed by dynamic
clamp experiments (Tilman Kispersky)