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

UE 5BN04 (« Neural Networks ») S. Charpier (ICM) stephane.charpier@upmc.fr Basic knowledge: I ion < 0 inward flow of cations: depolarization Driving force I ion = g ion .(V m - E ion ) I ion > 0 outward flow of cations: hyperpolarization & D V m = I ion . 1/G m ( or .R m ) 1

UE NB045 (Neural networks) S. Charpier stephane.charpier@upmc.fr Intrinsic plasticities or How neuronal excitability is modified as a function of past activity 2

Neuronal integration and the concept of synaptic & intrinsic plasticity: Basic equations ~ Postsynaptic channel receptors Before : W syn : I syn = g syn .(V m - E syn ) & D V syn = I syn . 1/G m K, non-synaptic ion channels After : W’ syn : I syn = g’ syn .(V m - E syn ) & D V syn = I’ syn . 1/G m Output V th D V m D V syn : D V syn = g syn .(V m - E syn ) . ____ 1 G m ( , ~ t , ~V m , Ca 2+ …) D V syn t m , l V th , I/O relation… 3

o Intrinsic plasticities vs synaptic plasticities: induction, expression and specific consequences o Indirect discovery in the hippocampus o Definition of « intrinsic excitability » and parameters (quantification) o 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

What are the basic differences (and common features) between synaptic and intrinsic plasticities Long-term potentiation Synaptic plasticity Control (LTP) psp’ = n.p.q Cond. psp = n.p.q Long-term potentiation of Intrinsic plasticity intrinsic excitability (LTPie) Cond. Or activity-dependent 5 modulation

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…) 6

Already described in the first paper on LTP! How to explain the dissociation? 7

Already described in the first paper on LTP! 8

How to define “excitability”? ( required to be quantified !) Louis Lapicque (1926) (first intracellular record in 1939) « 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. » Today 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. 9

V m, V th, D V th, AP lat., 1/G m, t m, g, I th, Dynamic features of firing Neuronal parameters defining intrinsic excitability (How to quantify intrinsic excitability at the soma ?) Time-dependent firing properties affected by excitability parameters “Dynamic” (depending on input changings) “Static” ( instantaneous ) Variability (SD of ISIs) F = g . i + a (+ adaptation) i s = - a / g Vth (mV) D Vth (mV) Vm t 1 (ms) Slope ( g = gain) t m = Rm . Cm Threshold ( Is = sensitivity) V(t) = I m . R m [1 – e -t/Rm.Cm ] 10 D V th = I th . R m

In sum… Subthreshold: Vm (mV); Vth (mV); D Vth; Rm (rest); Gm (~Vm; kinetics); t m 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) 11

Different forms of intrinsic plasticities result in different functions Homeostasis: normalization of firing Potentiation or depression ( ~ learning-like) + + 12

Short-term intrinsic plasticity => Kinetics of existing ion channels Long-term intrinsic plasticity => expression/Ca 2+ 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

Weak excitability of striatal neurons 15 Wilson CJ, Kawaguchi Y. 1996; Mahon, Deniau & Charpier, 2004; Charpier et al 2020

Slow kinetics of inactivation and recovery from inactivation of I As C.dV/dt = − (I Na + I K + I leak + I Kir + I Af + I As + I Krp + I NaP + I NaS + I syn + I noise ) + I inj Delayed firing Slow ramp depolarization ~-60 mV I depol I k Rate of activation Absolute value Rate of inactivation Progressive decrease in As current Slow recovery from inactivation 16 Mahon et al., 2000a,b, 2003, 2004

What is expected if a new excitation occurs while IAs does not fully recover? 17

The slow kinetics of recovery from inactivation of IAs incease firing and reduce AP latency Increase in intrinsic excitability In vivo In silico D t decreases with the rate of recovery  18  The slope depolarization decrease in parallel with the rate of recovery Mahon et al., 2000a,b, 2003, 2004

What could be the consequences on the processing of cortical inputs? 19

Intrinsic plasticity in striatal neurons facilitate cortico-strital synaptic transmission without modifying synaptic strength slope epsp => Vth Voltage window - 66 mV - 53 mV Voltage window 20 Mahon et al., 2000a,b, 2003, 2004

Intrinsic plasticity in striatal neurons increases the efficiency of desynchronized synaptic inputs ’ ’ 21 Mahon et al., 2000a,b, 2003, 2004

Long-term intrinsic plasticity: Homeostasis process 22

Homeostasis (?)  Primary cultures of visual Cortex neurons (pyramidal)  Control, 2.5 – 48h TTX, wash  CNQX, AP5, bicuculline After deprivation of activity:  Increase in neuronal gain  Decrease in current threshold  Decrease in voltage threshold for AP 23 Desai et al., 1999a,b

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

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

Subcellular mechanisms No IP conditionnement Cdt + H7 (block PKA, Cdt + H89 PKC, CaMKII, Cdt + Calphostin-C (block PKA ) (block PKC) cGMP PK ) IP induction depends upon: Forskolin (+ AC )  Calcium signaling (inward flow & intracell concentration)  Adenylate cyclase  Protein Kinase A 27 Cudmore et al., 2004

The presumed experience-dependent mechanism: synthetic hypothesis Neuronal activity (Cdt) Voltage-gated Ca 2+ channels Ca 2+ intra (Ca 2+ influx) (0 Ca 2+ ; BAPTA) Calcium-Calmoduline (CaMKII ?) Adenylate-cyclase (activated by forskoline) Excitability cAMP Phosphorylation-down regulation Others ? PKA Canaux K+ (blocked by H89) 28