Molecular linking

of the brain to mind

INCF, Warsaw April 16, 2015

Leszek Kaczmarek, Nencki Institute, Warsaw

Human & mouse brain

A mind is the set of cognitive faculties that enables consciousness, perception, thinking, judgement, and memory—a characteristic of humans, but which also may apply to other life forms

Wikipedia

the cellular connectionist approach, which derived

from Cajal’s idea that memory is stored as an

anatomical change in the strength of synaptic

connections (Cajal, 1894). (In 1948 Konorski

renamed Cajal’s idea synaptic plasticity [the ability

of neurons to modulate the strength of their

synapses as a result of use (Konorski, 1948)].

Kandel, Dudai & Mayford, Cell, 2014

Human brain: 85 billions of neurons; mouse brain: 70 mln; over 1 000 connections for each one

Glutamate

Glu Receptor

c-Fos

The joint term learning and memory (L&M) refers to

an animal (or human) ability to respond adequately

to environmental signals that in either exact or

similar nature have been encountered before and

might have important consequences, such as

allowing to withdraw from dangerous or unpleasant

conditions (aversive learning) or, alternatively,

approach the positive ones (appetitive learning).

After: Konopka, Schütz & Kaczmarek, Neuroscientist, 2011

IntelliCage H.P.Lipp, Zurich

Knapska et al., Learn. Mem, 2006

Central amygdala in appetitive learning

Place PreferencePlace Avoidance

c-Fos drives TIMP-1 & MMP-9:

Extracellular (synaptic) proteolytic system

Based on: Michaluk & Kaczmarek Cell Death Differ., 2007

TIMP-1TIMP-1

MMP-9

Jaworski et al., J.Biol. Chem., 1999

Kaczmarek et al., EMBO J., 2002

Kuzniewska et al., Mol. Cell. Biol., 2013

Ganguly et al., J.Biol.Chem., 2013

Gawlak et al., Neuroscience, 2009

MAP-2

MMP

activity

NR1

Appetitive conditioning is defective in MMP-9 KO

Knapska et al. J. Neurosci., 2013

Central amygdala-dependent appetitive conditioning

requires MMP-9 activity

. .

Knapska et al. J. Neurosci., 2013

Synaptic plasticity requires MMP-9

MMP-9

Michaluk et al., J. Neurosci., 2009; J. Cell. Sci., 2011;

Szepesi, et al., PLoS One, 2014

Rolipram+forskolin+picrotoxin

Before

40 min.

40 min.

w/o MMP-9

Glutamate GluA1 Receptor

Glutamate GluA1 Receptor

Knapska et al.,

PNAS, 2012

0 min

15 min

Stawarski et al.,

Biomaterials, 2014

How much do we know?

PNAS, 2013

How much do we know?

PNAS, 2013

Christ Church College Oxford

Michaluk et al. J. Neurosci. 2009

MMP-9 gene may be associated

with psychiatric disorders

Rybakowski et al., Schizophr. Res., 2009

& NeuroMolecular Medicine, 2009

-1562 C/T polymorphism affects MMP-9 gene expression

Samochowiec et al., Brain Res, 2010

0

10

20

30

40

50

60

Control, N=136

Alcoholics,N=139

Bipolar, N=416

Control, N=558

Schizophrenia,N=432

% of people with either T/T or T/C genotype, resulting in a higher expression

P=0.03P=0.03

P=0.001

High MMP-9 activity levels in Fragile X Syndrome are lowered

by minocycline that produces improvement

Bilousova et al., J. Med. Genet., 2009

� Fmr1 gene mutation is the

most common cause of

hereditary intellectual

disability in boys (IQ 20-70)

� Other symptoms: autistic

spectrum disorders,

behavioral disorders

� Epilepsy (25%)

� Neurons exhibit numerous

long, filopodia-like immature

dendritic spines

� FMRP KO mice reproduce the

human phenotype

Dziembowska et al.,

Am J Med Genet Part A, 2013

Minocycline treatment for 3 months in children with FXS

resulted in greater global improvement than placebo. Leigh et al., J Dev Behav Pediatr., 2013

MMP-9 mRNA

FMRP Co-localization

Janusz et al., J. Neurosci., 2013

M.Stefaniuk & M. Stawarski

Imaging the Brain

before clearing after clearing

clearing (CUBIC reagent)

Light-sheet fluorescence microscopy

is our choice for Method of the Year

2014 for its ability to image three-

dimensional biological samples at

high speed and with low toxicity.

Knapska i wsp., PNAS, 2012

Seeing the mind: Transgenic „Venus” rat to map

functional connectomics

Nencki Institute: E.Nikolaev, B.Kaminska, T.Werka, A.Szklarczyk, J.Jaworski, J.Dzwonek, P.Okulski, K.Duniec,

M.Rylski, E.Knapska, G.Wilczynski, F.Konopacki, M.Balcerzyk, P.Michaluk, A.Kowalczyk, V.Lioudyno,

L.Kolodziej, T.Gorkiewicz, R.Amborska, M.Gawlak, E.Wilczek, K.Duniec, Z.Lasiecka, I.Figiel, M.Wawrzyniak,

M.Yeghiazaryan D.Owczarek, K.Radwanska, J.Wlodarczyk, A.Walczak, M.Mikosz, Z.Szepesi, M.Chaturvedi,

K.Kalita, B.Kuzniewska, M.Stawarski, M.Stefaniuk, M.Dziembowska, K.Lepeta, O.Sakharczuk, K.Ganguly,

B.Pijet, A.Suska, A.Janusz, J.Milek, D.Gierej, A.Kaliszewska, M.Kossut

Szczecin: J.Samochowiec et al.

Poznan: J.Rybakowski et al. , Adamiak et al..

Wroclaw: J.Mozrzymas, G.Wiera et al.

Magdeburg: H.J.Matthies, W.Tischmeyer, M.Krug, W.Zuschratter, R.Frischknecht, M.Heine, A.Bikbaev

Oslo: O.-P.Ottersen

Bordeaux: D.Choquet, L.Mikasova, L.Groc, E.Hosy

Geneve: D.Muller, M.De Roo

Groton, PA: C.Strick

Los Angeles: R.Costa, A.Matynia, A.Silva

New York City: V.Nagy, O.Bozdagi, G.Huntley

San Francisco: Z.Werb , M.Sheng Montreal: S.Hanessian Rome: T.Petrucci

Heidelberg: W.Konopka, G.Schutz et al.

Milton Keynes: M.G.Steward, N.Medvedev

Zurich: H.P.Lipp, D.Wolfer

Davis & Sacramento: D.I.Pretto, M.J.Leigh, N.Gabriel, B.Durbin-Johnson, R.J.Hagerman, F.Tassone

Marseille: S.Rivera, M.Khrestchatisky

Rome & Leuven: C.Bagni, L.Paccini

College Station, TX: S.Maren

Jerusalem: E.Nelken

Goettingen: H.Ehrenreich, B.Stepniak, L.de Hoz

Bergen: C.R.Bramham

Lausanne: C.Sandi et al.