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Neurofiziologie -curs

Noiuni introductive- organizarea


sistemului nervos (SN) Cap. 10
Excitabilitate- noiuni generale
Generarea, transmiterea i
procesarea semnalului in sistemul
nervos
Fiziologia senzorial
Medical Physiology- W.F.Boron
Target Audience. We wrote Medical
Physiology primarily as an
introductory text for medical students,
although it should also be valuable for
students in the allied health
professions...
Noiuni introductive
Organizarea morfofuncional a
sistemului nervos
Macroscopic
Microscopic
Funcional
Noiuni introductive
Sistemul nervos (s.n.) cel mai complex
sistem din orgs. mediaz comportamentul de
la micrile simple i percepia senzorial
pn la nvare, memorie i contiin.
Este organul minii i rspunztor pentru
capacitatea uman de invenie, descoperire
i limbaj.
De fapt, cea mai important funcie, capaci-
tatea creierului uman de a gndi este greu
de neles.
Organizare morfofuncional a SN
Macroscopic
Somatic
-sistem nervos central
Vegetativ
-sistem nervos periferic (autonom)
Microscopic
-celule: neuroni
-celule: celule gliale sinapse
-teoria neuronal H. von Waldeyer.1891
-bariera hemato-encefalic
-relaii metabolice
Aspectul vizual

Imagine prin
spectrul de
difuziune- harta
fibrelor nervoase

http://www.sciencemag.org/content/335/6076/1628).
Gigandet X, et al. Estimating the Confidence Level of White Matter
Connections Obtained with MRI Tractography. PLoS ONE 3(12): . (2008)
Funcii principale ale
neuronului i
celulelor gliale
-metabolism energetic
-sinteza molecular
-transport-anterograd
-retrograd
-coducere
Compartmentalizarea neuronal
Neuronii sunt polarizai i au proteine
membranare distincte pt. fiecare domeniu
al neurilemei.
Sinteza proteinelor apare, n special n
corpul neuronal, mai puin in dendride RE
neted i rugos, ap. Golgi; este absent n
axon.
Mitocondria: prezent in corpul celular,
butonul terminal, este traficat in axon.
Transportul axoplasmatic antero- i
retrograd al moleculelor n vezicles de-a
lungul microtubulilor este mediat pri
microtubule-associated proteins (MAPs ):
1. kinezina pentru transp. anterograd-
enzime, proteine
2. Dyneina pentru transport retrograd:
NGF, alti factori de cretere, molecule
captate din mediul extracelular.
Transport anterograd- 400 mm/zi
retrograd 200-300 mm /zi
Quantum content
Circulaia cerebral -bariera hemato-encefalic
- bariera hemato lichidian

Lungimea total a capilarelor cerebrale- 400 mile


Distana neuron-capilar - 20 m
Cerebrospinal fluid (CSF)

CSF distributed in
-ventricles of the brain
-cisterns around the
outside of the brain
-subarachnoid space
around both the brain and
the spinal cord

Volume = 150 ml, daily production = 500 ml


Formation of CSF: 2/3 as secretion from the choroid plexuses in the 4
ventricles, but mainly in the 2 lateral ventricles; 1/3 as secretion by the
ependymal surfaces of the ventricles and by the arachnoid membranes
Function:
mechanical protection;
distribution of neuroendocrine factors
volume buffer: regulate ICP when tissue/ intracranial blood volume rises
Monroe-Kelly doctrine: V-CSF+V-blood+V-brain tissue = const.
Organizare morfofuncional a SN
Suportul genetic al SN

-Genomul uman- cca. 22.000 gene

-14.000 gene exprimate n dezvoltarea


i funcionarea creierului
Organizarea funcional a SN
Creierul holistic
This neuroepigenetic view suggests that
DNA, RNA and protein each influence
one another to produce a holistic
cellular state that contributes to the
formation and maintenance of memory,
and predicts a parallel and distributed
system for the consolidation, storage
and retrieval of the engram.
Marshall P. Bredy T W. Cognitive neuroepigenetics: the next evolution in our understanding of
the molecular mechanisms underlying learning and memory?. NPJ Sci Learn. 2016.
Epigenetic mechanisms have been suggested to
have roles in neuroplasticity, in particular
with regard to learning and memory forma-
tion, and in a range of neural diseases. In
addition to epigenetic marks, the human
genome also contains large-scale compart-
mentalized structures that might also
influence neuroplasticity and neural disease.
These structures result from variations in the
amounts of GC% and in the timing of DNA
replication and give rise to longitudinal
differentiation (light and dark bands) along
chromosomes after the appropriate staining.
Epigenetic modifications, such as
methylation, acetylation, or phospho-
rylation of histone proteins or
methylation of the DNA, can cause
changes to chromatin structure. These
changes in chromatin structure may
alter the binding of transcription
factors or enhancer element binding
proteins to promoter sites, thereby
modifying gene transcription patterns
Watanabe Y et al. Epigenetic basis of neuronal plasticity: Association with
R/G-band boundaries on human chromosomes. Neuroepigenetics 7 (2016)
Excitabilitate- noiuni generale

Excitabilitate - capacitatea
(condiia) unui sistem viu de a
capta semnale specifice, ca form
de actualizare a informaiei,
necesar organizrii lui ntru
adaptabilitate i continuitate.
Leon Zgrean
Optogenetics integrates genetic targeting
and optical stimulation to achieve
temporally precise manipulation of
genetically and spatially defined cell types
in intact tissue, and has influenced the
study of the central nervous system and
other systems across a broad range of
model organisms and behaviors.

Mattis JGrdinaru V. Nat Methods. 2014


Mecanisme celulare i
moleculare ale
excitabilitii
NIH scientists uncover genetic
explanation for frustrating syndrome.
www.nih.gov/news-events/news-releases/nih

Scientists at the NIH have identified a


genetic explanation for a syndrome
characterized by multiple frustrating and
difficult-to-treat symptoms, including
dizziness and lightheadedness, skin flushing
and itching, gastrointestinal complaints,
chronic pain, and bone and joint problems
JJ Lyons et al. Elevated basal serum tryptase identifies a multisystem disorder
associated with increased TPSAB1 copy number. Nature Genetics. 2016.Oct 17
The phenomenon of animal electricity is
central to the understanding of physiological
processes. Throughout this book, we will
describe many basic functions of tissues and
organs in terms of electrical signals mediated
by cell membranes. Whereas electrical
currents in a metal wire are conducted by the
ow of electrons, electrical currents across
cell membranes are carried by the major
inorganic ions of physiological uids: Ca2+,
Na+, K+, Cl, and HCO3 .
Boron and Boulpaep. Medical Physiology. 2012
La nivelul
cel mai
elementar,
noi nu
suntem o
reacie
chimic ci
o sarcin
electric...
Cmpul electromagnetic este realitatea
fizic cu care suntem n contact permanent
i nemijlocit, dei nu avem simuri pentru a
o percepe. n odaia n care stm, n parcurile
n care ne plimbm, n noi nine, totul este
plin de cmp electromagnetic, n fiecare
moment, datorit cmpului electromagnetic,
fiecare cut a fiinei noastre este ptruns de
toate melodiile care se cnt pe Pmnt, ba
i de oapte din afara lui, rostite poate cu
miliarde de ani n urm.
A.ugulea- Cmpul electromagnetic? Ed. Agir, 2011
Hans Berger
de la telepatie la EEG -1926
Interaciunea
stimul - receptor - rspuns

Receptor
Procesor
fizic
chimic
stimul rspuns
?
Due to its ability to give rise to
spontaneous activity, the brain does
not simply process information but
also generates information.
...spontaneous neuron activity, far
from being mere noise, is actually the
source of cognitive abilities.
...the source of spontaneous neuron
activity (noise), has never been
identified and has been assumed to
result from brains imperfections.
Gyrgy Buzski
ISI Web of Science Results found (no. of papers): 274
Citation Author: Buzsaki G
Report Sum of the Times Cited: 27. 404

Average Citations per paper : 100

h-index (Hirsch index): 86


Published Items in Each Eear Citations in Each Year
Premise
excitabilitate

permeabilitate
identitate evoluie
selectiv
membranar

adaptabilitate

Interrelaiile dintre propietile membranei celulare


i principalele dimensiuni ale existenei
sistemelor biologice
O2
CO2
Molecule N2
hidrofobe Subst.
steroidice
Molecule Ap
mici Glicerol
nepolare Uree
Molecule
mari Glucoz
Zaharoz
nepolare
Na+, H+, K+
Ioni Ca2+, Mg2+
HCO3-, Cl-
Halobacterium salinarium
Sistemul de transport ionic
membranar (STIM)
- Canale ionice transport pasiv
- Transportori ionici
- Cotransportori transport activ
Simportori secundar
Antiportori
- Pompe ionice transport activ
primar
Mecanisme ale transportului ionic
Por (canal fr poart)
Aquaporina
Permeabilitatea membranei
celulare depinde de:
-interaciunea ionilor cu apa
-bistratul lipidic membranar
-canale ionice
filtru de selecie ans de selecie
K+

O O
O O
O O

citosol
K = 0,133 nm vestibul
Na = 0,095 nm por
Filtrul de selecie
Canale ionice
Canale ionice controlate (gated)
- controlate fizic - de voltaj
- mecanic
- termic TRP
- controlate chimic:
- neurotransmitori
- ioni, H+
- produi metabolici .a
Canale ionice fr poart
necontrolate (nongated)
Canale ionice cu poart
Particulariti:
-permit un flux controlat rapid
-particip la generarea, transmiterea sau
modularea potenialului de aciune
-prezint o diversitate mai mare
-au fost descoperite primele
-reprezint principala int terapeutic
Canal (por cu poart)

Mecanisme de funcionare
1 2

S
S

S
S

S
S 3
6

5 4

Etapele transportului unui solvit (S) prin


intermediului transportorului membranar
Boron and Boulpaep. Medical Physiology. 2012
Canale ionice controlate de voltaj
Canale de Na+ voltaj- dependente
identificat 1970

P P
Structura canal de Na voltaj dependent
Curent de poarta
__ TTX _ _ SCTX
Extracelular _ _

+ + +

+ + +
+

Por

+
Bistrat lipidic

+
TX
B LA
+
+

+
+
Senzor de voltaj
Poarta
Canale de Na+ voltaj- dependente

extracelular

membran
celular
+

poart de poart de
activare inactivare
REPAUS (nchis)

ACTIVAT (deschis)

INACTIVAT (nchis)

+
Canale voltaj-dependente
- Canale pentru Na+
- 10 gene pt. Na V
- distribuie 30-10000/m
- structur
-subunitatea - (1- 9/ Nav 1- 9)
-1800-2000 aa
- formeaz porul canalului
-subunitatea
- controleaz transportul ionic
- ancoreaz canalul n membrana
celular
Canale de Na+ voltaj- dependente
- rol
- transport - 107 ioni/sec./canal
- faza depolarizare a PA
- conducerea PA in fibrele nervoase
-canalopatie
-paralizie periodic hiperkaliemic
inactivarea ntrziat a Na V muscular
Canale de Na+ voltaj- dependente
Distribuie, rol

Nav 1-3, Nav 6-9 n SNP, SNC cu rol


in durere pot fi mai multe tipuri pe
acceai celul nervoas
Nav1.6 n celule imune, microglia i
macrofage
Nav 4-5 n m. scheletic i miocard
Canale pentru K+
voltaj-dependente
- diversitate genetic - 200 gene
(peste 78 la om)
- rol:
- rectificare
- controlul duratei p. a.
- modularea excitabilitii
celulare prin re-/hiperpola-
rizarea membranei
Canale pentru K+ voltaj-dependente
- clasificare
-cn.K tip M - Ach
-cn.K dependente de ATP
- cel.-pancreatice- ATP
nchiderea cn. K depolarizare
-miocardice- ATP/ADP
activarea cn K hiperpolarizare
-cn.K dependente de Ca cel
pancreatice
- cn.K+ dependente de vol. cel.
TTX Novocaina

TEA
Saxitoxin

Variaia PA indus de blocanti


Mordecai P. Blaustein. Cell. Physiol.and Neurophysio. Ed. Elsevier 2012
Canale pentru Calciu voltaj-dependente
- distribuie - 100/m
- transport - 180000 ioni/sec./cn
-tipuri: L - activat la potenial nalt pozitiv
- blocani: - dihidropiridine:
nimodipin, nifedipin, nicardipine;
- fenilalchilamine:
verapamil, gallopamil;
- benzotiazepine :
diltiazem
- modulat - AMP c
Canale pentru Calciu
voltaj-dependente
Canalopatii legate de canale de tip L
-cecitate congenital diurn - hemeralopie
-cecitate congenital nocturn- nictalopie
Canale de Calciu voltaj-dependente
-Tipuri:
T: - activat la potential negativ
- conductan mic
- rol -pacemaker
- blocant- mibefradil
N: - activat la voltaj intermediar
- blocant - -conotoxin
P/Q: P-cel.Purkinje; blocant- -agatoxin
Q- cel granulare; - agatoxin
Canale ionice controlate mecanic
situs de
extrcelular ancorare

membran
celular

intracelular

protein
poart
fibrilar

Cnd celula este alungit, proteina fibrilar


fixat pe situsul de ancorare deschide
poarta canalelor ionice
situs de ancorare intracelular

membran celular

protein fibrilar

extrcelular

membran
celular

intracelular

Cnd distana dintre dou celule nvecinate


crete, proteina fibrilar fixat pe situsul de
ancorare dintr-o celul, deschide poarta
canalelor ionice din celula nvecinat
Canale ionice controlate termic
(vezi superfamilia TRP)
0
TRPV1 - temperatura >43 C
0
TRPM8 temperatura 8-28 C, mentol
TRPA1 usturoi, mustar
Tranzient Receptor Potenial
TRP superfamily ion channels
(Superfamilia canalelor ionice cu
potenial tranzitoriu de receptor)
-sunt activate de diferii factori:
-fizici: lumin, variaii de
temperatur;
-chimici: Vaniloizi , Melastatin,
Policistin, Mucolipin i Anicrin
-permit transportul cationilor,
n special Ca i Na
TRP superfamily ion channels
TRPC (canonical): TRPC1, TRPC2,
TRPC3/6/7, TRPC4/5
-sunt canale pentru Ca i/sau Na
-sunt activate de PLC activat prin:
a)cuplarea receptorilor de ctre
liganzi =receptor operated channels -
DAG- TRPC3, TRPC6- vasoconstricie
b)Ca din depozitele celulare
= store-operated channels
transport membranar
canal
proteic transportori

bistrat
Gradient de
lipidic concentraie

difuzie
mediat mediat de mediat de
de canale transportori pompe
simpla transp. pasiv transport activ

adaptat dup MOLECULAR BIOLOGY OF THE CELL. 2008


COTRANSPORTORI
COTRANSPORTORI
POMPE IONICE
particulariti funcionale
- transport activ-ioni, mol. organice
- implic reacii enzimatice
- rat mic de transport
Pompa de Ca

A
Extracel

Intracel.

N Situs de legare a Ca2+

Calmodulin
Situsul ATP-azei
Situsul de legare a ATP C
Funciile transportului ionic

-excitabilitate
-cuplare metab.-excitabilitate
-reglare metabolic
-metab. neurotransmitori
-presiune osmotic,
volum celular
Transport ionic membranar
Concluzii
Interrelaii excitabilitate-
metabolism
Distribuia sarcinilor electrice
RT [X]i
Vm = ln
+20 zXF [X]o

depolarizare Nerst
repolarizare
Pm (mV)

depolarizare

- 60 hiperpolarizare repolarizare
timp (ms)
Variaia potenialului de membran n raport cu
activitatea celulei nervoase
Potenial de aciune

PA
0 mV

Na+
K+
50
Canale ionice Ach
Schema generala a receptorului de NMDA
N-metil-D-aspartat; PCP- fenciclidina; MK-801 - dizocilpina
A 200 nM, CA3
Kainat
20 M, CA3
Bicuculin

CONTROL CRIZ CRIZ


EVOCAT SPONTAN
Echilibrul excitatie inhibitie/relaia agonist-antagonist
Legenda pt. relaia agonist-antagonist
A. Administrarea de Kainat (agonist glutamat-
ergic) induce dup cca. 10 min activitate
electric epileptiform (aee), iniial, dup
stimulare electric, ulterior, n mod spontan.
B. Administrarea de Bicuculin (antagonist
GABAergic), induce dup cca. 10 min activitate
electric epileptiform (aee), iniial, dup
stimulare electric, ulterior, n mod spontan.
Inregistrrile aee au fost realizate pe seciuni de
creier animal, perfuzate cu lichid cefalorahidian
artificial, in care au fost administrate kainat i
bicuculin.