the abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer...
TRANSCRIPT
![Page 1: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/1.jpg)
The abrupt transition from theta to The abrupt transition from theta to hyper-excitable spiking activity in hyper-excitable spiking activity in
stellate cells from layer II of the medial stellate cells from layer II of the medial entorhinal cortexentorhinal cortex
Horacio G. RotsteinHoracio G. RotsteinDepartment of Mathematical SciencesDepartment of Mathematical Sciences
New Jersey Institute of TechnologyNew Jersey Institute of TechnologyNetwork Synchronization: From dynamical systems to neuroscience Network Synchronization: From dynamical systems to neuroscience
Leiden (NL) - May 27, 2008Leiden (NL) - May 27, 2008
![Page 2: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/2.jpg)
Collaborators
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
![Page 3: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/3.jpg)
Entorhinal 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)
![Page 4: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/4.jpg)
Stellate 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.
![Page 5: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/5.jpg)
Subthreshold 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)
![Page 6: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/6.jpg)
SCs: 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)
![Page 7: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/7.jpg)
SCs – 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.
![Page 8: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/8.jpg)
SC 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?
![Page 9: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/9.jpg)
SC biophysical model
![Page 10: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/10.jpg)
SC biophysical model
![Page 11: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/11.jpg)
SC biophysical model
![Page 12: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/12.jpg)
Subthreshold oscillations (STOs) and spikes in the SC model
![Page 13: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/13.jpg)
STOs generated by persistent sodium channel noise in the SC model
![Page 14: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/14.jpg)
Subthreshold Regime: Reduction of Dimensions
Multiscale analysis: Identification of the active and inactive currents Identification of the appropriate time scales
![Page 15: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/15.jpg)
Subthreshold Regime: Reduction of Dimensions
Multiscale analysis: Identification of the active and inactive currents Identification of the appropriate time scales
![Page 16: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/16.jpg)
Subthreshold regime: reduced SC model
SC biophysical model Subthreshold regime
![Page 17: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/17.jpg)
Subthreshold regime: reduced SC model
![Page 18: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/18.jpg)
Subthreshold regime: reduced SC model
![Page 19: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/19.jpg)
Subthreshold regime: reduced SC model
SC biophysical model Subthreshold regime
![Page 20: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/20.jpg)
Subthreshold regime: reduced SC model
![Page 21: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/21.jpg)
Nonlinear Artificially Spiking (NAS) SC model
![Page 22: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/22.jpg)
Nonlinear Artificially Spiking (NAS) SC model
![Page 23: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/23.jpg)
Nonlinear Artificially Spiking (NAS) SC model
![Page 24: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/24.jpg)
Inhibitory inputs can advance the next spike by “killing” an STO.
![Page 25: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/25.jpg)
Transition 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)
![Page 26: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/26.jpg)
Minimal S-I network model
![Page 27: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/27.jpg)
Minimal 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
![Page 28: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/28.jpg)
Minimal 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
![Page 29: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/29.jpg)
Minimal SC network model (no inhibition)
A small increase in the SC recurrent synaptic conductance causes an explosion of the SC firing frequency
![Page 30: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/30.jpg)
Minimal SC network model (no inhibition)
A small increase in the SC recurrent synaptic conductance causes an explosion of the SC firing frequency
![Page 31: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/31.jpg)
Minimal S-I network model
A small increase in the inhibitory input to the SCs brings their frequency back to the theta regime
![Page 32: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/32.jpg)
Single 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.
![Page 33: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/33.jpg)
Single SC + autapse (no inhibition)
Effects of changes in the maximal conductances
![Page 34: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/34.jpg)
Single SC + autapse (no inhibition)
Effects of changes in the maximal conductances
![Page 35: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/35.jpg)
Single SC (no autapse - no inhibition)
![Page 36: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/36.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 37: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/37.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 38: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/38.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 39: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/39.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 40: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/40.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 41: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/41.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 42: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/42.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 43: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/43.jpg)
Single SC (no autapse - no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 44: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/44.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 45: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/45.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 46: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/46.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 47: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/47.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 48: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/48.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 49: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/49.jpg)
Single SC + autapse (no inhibition)
The abrupt changes in the SC firing frequency are the result of phasic (synaptic) and not tonic excitation
![Page 50: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/50.jpg)
Single SC + autapse (no inhibition)
Tilman Kispersky & John White
Dynamic clamp experiments
![Page 51: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/51.jpg)
Dynamic clamp experiments
Voltage record of a stellate cell coupled to itself.
Inset: close up view of a single burst
Under control conditions
![Page 52: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/52.jpg)
Dynamic 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)
![Page 53: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/53.jpg)
Dynamic clamp experiments
Freq. vs. current under control conditions
![Page 54: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/54.jpg)
Dynamic clamp experiments
![Page 55: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/55.jpg)
Minimal S-I network model
![Page 56: The abrupt transition from theta to hyper- excitable spiking activity in stellate cells from layer II of the medial entorhinal cortex Horacio G. Rotstein](https://reader036.vdocument.in/reader036/viewer/2022062713/56649cc15503460f94987fe5/html5/thumbnails/56.jpg)
Summary
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)