neuronal plasticity

Aspectos Moleculares y Celulares de la Función Neuronal
Plasticidad Intrínseca y Sináptica
Marcela S. Nadal, Ph.D
Grupo de Física Estadística e Interdisciplinaria
Escuela "José A. Balseiro" 2009
Modelado en Neurociencias
Instituto Balseiro - Centro Atómico Bariloche
San Carlos de Bariloche, 5 al 30 de octubre de 2009
neuronal plasticity allows for behavioral adaptation
intrinsic
•
•
•
•
•
•
•
neuronal plasticity
firing threshold, firing patterns
subthreshold Vm: Ih, IA, leak
channels
synaptic integration
Ca2+ signaling
metabotropic receptors
kinases/phospatases and 2nd
messengers
ion channel localization
synaptic
•
•
•
•
•
•
structural
•
•
•
•
rewiring
spine formation
spine morphology/motility
neurogenesis
Ca influx, p and N (pre)
quantal size - N˚ of R (post)
NMDA channels: Ca2+
signaling
kinases/phospatases and
2nd messengers
metabotropic receptors
receptor turnover
mecanismos de almacenamiento de la
informacion: cambio localizado vs global
Zhang & Linden 2003
functional recovery in mouse visual cortex
after focal retinal lesions
Keck, 2008
number of new persistent spines increases
with functional recovery
layout of the whisker sensory pathway
Diamond, 2009
rodent barrel cortex
somatosensory
barrel cortex S1
primary motor cortex
Petersen, 2007
secondary somatosensory cortex
Functional Mapping of the Barrel Cortex
barrels: cortical representation of whiskers in rodents
sensory adaptation
experience-dependent map plasticity
Polley, 1999
plasticity of an individual WFR of an adult rat
in response to changes in the habitat
boring
stronger and more
interesting stimuli
whisker functional representation (WFR): a population measure defined as
the cortical area activated by single whisker stimulation
intrinsic
•
•
•
•
•
•
•
neuronal plasticity
firing threshold, firing patterns
subthreshold Vm: Ih, IA, leak
channels
synaptic integration
Ca2+ signaling
metabotropic receptors
kinases/phospatases and 2nd
messengers
ion channel localization
synaptic
•
•
•
•
•
•
structural
•
•
•
•
rewiring
spine formation
spine morphology/motility
neurogenesis
Ca influx, p and N (pre)
quantal size - N˚ of R (post)
NMDA channels: Ca2+
signaling
kinases/phospatases and
2nd messengers
metabotropic receptors
receptor turnover
other receptors
sensorial stimuli
metabotropic
receptors
Na+, Ca+2
K+, Cl-
voltagegated
channels
neurotransmitters
ionotropic
receptors:
iGluR, GABA
other
signaling
cascades
enzymes
contraction
channel gating
gene expression
secretion of neurotransmitters
calcium sensors
signaling proteins
enzymes
gene expression
retrograde signaling
Activity-dependent eCB release inhibits neurotransmitter release
from synapses of both pyramidal cells (Pyr) and
cholecystokinin (CCK)+ interneurons
receptores metabotrópicos
from Hille, 2001
hay mas de mil receptores
metabotropicos:
Phylogenetic trees of
human endoGPCRs
Vassilatis D K et al. PNAS 2003;100:4903-4908
patterns of receptor/G protein coupling
gene expression by G proteins and protein kinases
effects of Ca2+ and calmodulin on neuronal plasticity
Modulation of
VG channels
intrinsic plasticity
synaptic plasticity
neuronal substrates of CaMKII
long term synaptic plasticity mechanism
modulación de canales iónicos
– dependencia de voltaje, tiempo
– neurotransmisores a través de receptores
metabotrópicos (GPCR)
– mensajeros lipídicos: AA, PIP2
immediata, directa:
ms a pocos segundos
transiente:
segundos a minutos
– sistemas de señalización por calcio
– otros sistemas de kinasas/PP
prolongada:
horas a días
– inducida por neurotransmisores y
protocolos que fortalecen o debilitan
sinapsis a largo plazo
– cambios en la densidad o localización de
canales
– asociación con subunidades auxiliares
– síntesis de proteínas
persistente
bidirectional modification of Kv channel inactivation by lipids
(Arachidonic Acid)
the phospholipid PIP2 relieves inactivation of the Kv channel
modulation of Kv4 currents by the auxiliary subunit DPPX-S
Kv4.2
200 nA
T0.5= 27.4ms
Imax at 40mV (mA)
10
8
Kv4.2
6
Kv4.2 + DPPX-S
4
2
0
1
50 ms
1000 nA
3
4
5
6
7
8
time peak (ms)
1.0
G/Gmax
Kv4.2 + DPPX-S
T0.5= 10.0ms
2
0.8
0.6
0.4
0.2
50 ms
0.0
-80 -60 -40 -20 0
20 40
V (mV)
back propagation of AP in dendrites of CA1 hippocampal neurons
Na+
Ca2+
Ih
K+ sust.
ISA
soma
dendrite
action
potentials
Hoffman et al., 1997; Magee & Johnston, 1997; Migliore et al. 1999; Jonhston et al., 2000
A-type K+ currents affect the back propagating action potentials
in dendrites of CA1 hippocampal neurons
bAP
LTP
=
soma
EPSP
dendrites
Hoffman et al., 1997; Magee & Johnston, 1997; Migliore et al. 1999; Jonhston et al., 2000
Hebb's Law
– When an axon of cell A is near enough to
excite cell B and repeatedly or persistently
takes part in firing it, some growth process or
metabolic change takes place in one or both
cells such that A's efficiency, as one of the
cells firing B, is increased
"Neurons that fire together wire together."
critical window for spike timing dependent plasticity
different amounts and types of STDP evoked by
repeated pairing of pre- and postsynaptic action potentials
LTD
(CA1)
Sjostrom Nelson 2002
Induction of long term potentiation (LTP) in the hippocampus
After Bliss & Lomo, 1973
Tsien, 1996
Mice that lack NMDAR in CA1 have a defect in
LTP and in spatial memory
Mayford, 1996; Tsien, 1996
NMDAR electrical effects are divided in three IV curve regimes
Guy Major
Synaptic activation of NMDA receptors
causes local Ca2+ entry into a dendritic spine
long-term potentiation and long-term depression at the Schaffer
collateral–CA1 synapse depend on a series of calmodulin-regulated events
LTD in pyramidal neurons of the neocortex
LTD mediated by cannabinoid receptor CB1R
cellular signaling by CaMKs
Wayman et al., 2008
Structure and regulation of CaMKII
Lisman et al., 2002
The binding of Ca2+/calmodulin (CaM) causes the gate to open and the kinase to become active (star). The kinase can now be phosphorylated at threonine residue 286 (T286) by a neighboring subunit and this autophosphorylation can keep the gate open, even after dissociation of Ca2+/calmodulin. Irvine et al., 2006
CaMK activation by Long‐Term Potentiation
• CaMKII remains activated for at least one hour after LTP induction
• LTP increases CaMKII bound in spines
Wayman et al., 2008
Autophosphorylation of Thr286
• Decreases dissociation of bound Ca2+/Cam
• Ca2+ independent, persistent activity (30‐60%)
(until dephosphorylation) • promotes and stabilizes binding to PSD
synaptic strength of individual spines (suppressed by P of Thr305/306)
• is triggered by activity of NMDAR (CaMKII binds NR2B) • promotes P of AMPAR subunit GluR1
a mutation that eliminates phosphorylation of Thr 286 blocks LTP
Barria and Malinow, 2005; Lisman, 2002; Wayman et al., 2008
LTP induced by a pairing protocol requires CaMKII activity
Lisman, 2002
αCaMKII autophosphorylation is required for rapid memory formation (induction of LTP) than for memory storage (maintenance of LTP: requires protein synthesis)
The T286A αCaMKII mutant mice are impaired compared with wild‐type (WT) mice after training with one or three tone–shock pairings .
Irvine et al., 2006
Learning and memory are affected in animals
that express a mutant form of CaMKII
water maze platform
visible
hidden
α-CaMKIIT286A
α-CaMKII wt
Lisman et al., 2002
CaMKII affects cortical plasticity: the α-CaMKIIT286A animals
do not show the deprivation-induced plasticity of wild-type animals
From Gazewsky et al., 2000
NMDAR-dependent signaling in learning and memory
Cao et al., 2008
The Presence of Overexpressed αCaMKII‐F89G Leads to Larger LTP in Transgenic Mice
Wang et al., 2008
Chemical‐Genetic Approach
Alaimo et al., 2001
Wang et al., 2008
5 min
10 min
15 min
25 min
the initial 10 min period represents the critical time window during which both
potentiated synapses and short-term memory are in an especially labile state
and are sensitive to numerical increases in CaMKII activity
Wang et al., 2008
What temporal dynamics of activated CaMKII might underlie this critical time window? Wang et al., 2008
• Fear Conditioning Task: contextual or cued
‐ TONE: conditioned stimulus (CS): 85dB sound at 2800Hz ‐ SHOCK: unconditioned (aversive) stimulus (US): foot shock 0.75mA 2s
• Novel Object Recognition Task
10 months
hipocampus
amygdala
Days
Medial temporal lobe structures
Synaptic scaling is multiplicative
Adaptada de Turrigiano et al., 1998
Stuart et al. 2001
• Hay informacion en el AHP