UE 5BN04 ( Neural Networks ) S. Charpier (ICM) - - PowerPoint PPT Presentation

UE 5BN04 (« Neural Networks »)

• S. Charpier (ICM)

stephane.charpier@upmc.fr Basic knowledge:

1

Iion = gion.(Vm - Eion)

&

DVm = Iion . 1/Gm (or .Rm)

Driving force Iion < 0 inward flow of cations: depolarization Iion > 0

• utward flow of cations: hyperpolarization

Intrinsic plasticities

• r

How neuronal excitability is modified as a function of past activity

UE NB045 (Neural networks)

• S. Charpier

stephane.charpier@upmc.fr

2

3 DVm Vth

Before: Wsyn: Isyn = gsyn.(Vm - Esyn) & DVsyn = Isyn . 1/Gm After: W’syn: Isyn = g’syn.(Vm - Esyn) & DVsyn = I’syn . 1/Gm

DVsyn

: DVsyn = gsyn.(Vm - Esyn) . ____ Gm ( , ~t, ~Vm, Ca2+…) 1

Output

DVsyn Vth , I/O relation… tm , l

Neuronal integration and the concept of synaptic & intrinsic plasticity: Basic equations

K, non-synaptic ion channels ~ Postsynaptic channel receptors

• Intrinsic plasticities vs synaptic plasticities: induction, expression and specific consequences
• Indirect discovery in the hippocampus
• Definition of « intrinsic excitability » and parameters (quantification)
• Two main forms of intrinsic plasticity: homeostatic-like & memory-like

Different forms/examples of intrinsic plasticity:  Short-term intrinsic plasticity and the intrinsic memory of striatal neurons  Long-term intrinsic plasticity and homeostasis  Long-term intrinsic plasticity and learning: Visual cortex in vitro Bidirectional intrinsic plasticity in the barrel cortex in vivo

4

Cond. Synaptic plasticity Control Long-term potentiation (LTP) Intrinsic plasticity Cond. Long-term potentiation of intrinsic excitability (LTPie)

What are the basic differences (and common features) between synaptic and intrinsic plasticities

psp = n.p.q

Or activity-dependent modulation

5

psp’ = n.p.q

6

Specific consequences of intrinsic plasticity: IP

 IP directly affects the output function of neurons (AP or not) since it often operates at or near the soma  IP alters the firing probability of the neuron (changes in the neuron’function within its network)  IP has similar effect (positive or negative) on all synaptic inputs (whatever their origin, no synaptic specificity) affecting their ability of fire or not an AP  IP, contrary to synaptic plasticity (LTP…), does not require prolonged or strong stimulation, thus it can provide a cellular correlate for single-experience learning (single AP can be sufficient…)

7

Already described in the first paper on LTP! How to explain the dissociation?

8

Already described in the first paper on LTP!

How to define “excitability”? (required to be quantified!)

« Excitability is an abstraction. The measurable reality is the exciting stimulus: the action that causes the reaction to the object ... excitability is a reciprocal value of the exciting action. »

Louis Lapicque (1926) (first intracellular record in 1939)

Capacity (relative) of an excitable element to generate an action potential in response to a given excitatory stimulus. It depends on the "passive" electrical properties and the active membrane conductance that participate to the firing of the neuron.

Today

9

Vth (mV) t1 (ms)

Neuronal parameters defining intrinsic excitability (How to quantify intrinsic excitability at the soma ?)

tm = Rm . Cm

DVth (mV)

F = g . i + a is = - a / g

(+ adaptation) V(t) = Im . Rm [1 – e-t/Rm.Cm]

Variability (SD of ISIs)

Slope (g = gain) Threshold (Is = sensitivity)

Vm

“Static” (instantaneous) “Dynamic” (depending on input changings)

DVth = Ith . Rm

10 Time-dependent firing properties affected by excitability parameters Vm, Vth, DVth, AP lat., 1/Gm, tm, g, Ith, Dynamic features of firing

11

Subthreshold: Vm (mV); Vth (mV); DVth; Rm (rest); Gm (~Vm; kinetics); tm Suprathreshold: Input threshold (Ith); neuronal gain (g); firing paramaters: Spike latency; time- dependent variability, adaptation, trial-to-trial changes in spike rate and inter-spike intervals)

In sum…

Homeostasis: normalization of firing

Different forms of intrinsic plasticities result in different functions

Potentiation or depression ( ~ learning-like)

12

+ +

Short-term intrinsic plasticity => Kinetics of existing ion channels Long-term intrinsic plasticity => expression/Ca2+ modulation of ion channels In vitro => mechanisms In vivo => functional consequences Homeostatic or memory-like processes?

13

Short-term intrinsic plasticity: The role of temporal (kinetics) properties of (voltage-gated) active conductances in striatal neurons

14

15

Weak excitability of striatal neurons

Wilson CJ, Kawaguchi Y. 1996; Mahon, Deniau & Charpier, 2004; Charpier et al 2020

Slow kinetics of inactivation and recovery from inactivation of IAs

Mahon et al., 2000a,b, 2003, 2004

~-60 mV Rate of inactivation Absolute value

Slow recovery from inactivation

Rate of activation

C.dV/dt = − (INa + IK + Ileak + IKir + IAf + IAs + IKrp + INaP + INaS + Isyn + Inoise) + Iinj

16 Delayed firing Slow ramp depolarization Progressive decrease in As current

Ik

I depol

17

What is expected if a new excitation occurs while IAs does not fully recover?

The slow kinetics of recovery from inactivation of IAs incease firing and reduce AP latency

In vivo

Mahon et al., 2000a,b, 2003, 2004

In silico

18

• Dt decreases with the rate of recovery
• The slope depolarization decrease in parallel with the rate of recovery

Increase in intrinsic excitability

19

What could be the consequences on the processing of cortical inputs?

Intrinsic plasticity in striatal neurons facilitate cortico-strital synaptic transmission without modifying synaptic strength

Mahon et al., 2000a,b, 2003, 2004

• 66 mV
• 53 mV

slope epsp => Vth

Voltage window Voltage window

20

’ ’

Mahon et al., 2000a,b, 2003, 2004

Intrinsic plasticity in striatal neurons increases the efficiency

• f desynchronized synaptic inputs

21

Long-term intrinsic plasticity: Homeostasis process

22

Desai et al., 1999a,b

• Primary cultures of visual

Cortex neurons (pyramidal)

• Control, 2.5 – 48h TTX, wash
• CNQX, AP5, bicuculline

Homeostasis (?)

23 After deprivation of activity:  Increase in neuronal gain  Decrease in current threshold  Decrease in voltage threshold for AP

(+TEA, 4-AP, Cd)

Imbalance between sodium ( ) et potassium ( ) currents

Desai et al., 1999a,b TEA insensitive 4-AP sensitive Fast inactivating TEA sensitive Ik persistent (~delay rec) I Na+ I K+ 24 No change in passive membrane properties

Long-term intrinsic plasticity: Memory-like process

25

Potentiation in excitability of neocortical neurons in vitro

• Visual cortex slices
• Layer 5 pyramidal neurons
• CNQX, d-APV, bicuculline
• 60 depolarizing current pulses of 500ms (F= 30

Hz), every 4 s Cudmore et al., 2004 26 After conditioning:  Decrease in threshold current  Increase in Vm slope preceding AP  Decrease in spike latency  No change in Rm & Vm

Subcellular mechanisms

conditionnement Cdt + H7 (block PKA, PKC, CaMKII, cGMP PK) Cdt + H89 (block PKA) Cdt + Calphostin-C (block PKC) Forskolin (+AC)

Cudmore et al., 2004

No IP

27 IP induction depends upon:  Calcium signaling (inward flow & intracell concentration)  Adenylate cyclase  Protein Kinase A

Neuronal activity (Cdt) Ca2+ intra (Ca2+ influx) (0 Ca2+ ; BAPTA) Calcium-Calmoduline Adenylate-cyclase (activated by forskoline) cAMP PKA (blocked by H89)

Phosphorylation-down regulation Canaux K+

Excitability

Others ?

(CaMKII ?)

Voltage-gated Ca2+ channels 28

The presumed experience-dependent mechanism: synthetic hypothesis