The neuronal cell adhesion molecule ICAM-5

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THE NEURONAL CELL ADHESION MOLECULE ICAM-5

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REVIEW OF THE LITERATURE

1. ROLE OF NEURONAL IGSF ADHESION

MOLECULES AND NMDA RECEPTORS IN THE CNS

1.1. COMMONLY USED TERMS IN NEUROBIOLOGY

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amygdala within the brain temporal lobe, involved in emotion and memory processing

cerebellar vermis a structure between the cerebellar hemispheres cerebellum little brain, involved in motor control

cerebral cortex the outermost neural tissue surrounding the cerebrum (forebrain)

cerebral piriform cortex in telencephalon, involved in smell perception contextual fear conditioning a learning form in which the animal can associate the

stimulus and the aversive consequences of the stimulus corpus callosum a bridge between the right and left cerebral hemispheres corticospinal tract axons that connect the spinal cord and the cerebral cortex dendritic arborization dendritic outgrowth and branching

dendritic spines small protrusions in dendrites of the postsynaptic neurons, receive the information from the axons from presynaptic neurons, involved in mediating information forward diencephalon involved in regulation of the autonomic nervous system excitatory neurons neurons which release a neurotransmitter (glutamate) which

causes activation and/or depolarization of the postsynaptic neurons

excitotoxicity neuronal death caused by neurotransmitter receptor overactivation

glial cells astrocytes and oligodendrocytes, protect and support neurons in brain

growth cone a protrusion at the tip of an axon, forms contacts with the postsynaptic neurons

hippocampus in the telencephalon, involved in memory formation

hydrocephalus brain swelling

inhibitory neurons neurons which release a neurotransmitter (GABA) which causes deactivation and/or hyperpolarization of the postsynaptic neurons

locomotor activity movement from one place to another

long-term potentiation a long-lasting increase in synaptic transmission between two neurons, involved in learning and memory processing long-term depression a long-lasting decrease in synaptic strength, selective, can

weaken speciﬁc synapses

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mesencephalon the midbrain, involved in vision, hearing, motor control metencephalon contains pons and cerebellum, involved in regulating

breathing

myelencephalon contains medulla oblongata, also involved in regulating breathing

neocortex part of the cerebral cortex, involved in higher brain functions such as sensory perception and language

neural tube CNS develops from it in the embryo

neuron depolarization neuronal stimulation

neurotransmission neurotransmitter receptors are activated, can lead to long- term or short-term changes in synaptic strength

olfactory bulb in the forebrain, involved in smell perception prepulse inhibition in the acoustic

startle response

can be used in animals to study human neurological diseases having deﬁcits in sensorimotor gating radial maze task measures spatial learning and memory in animals radial migration differentiating neural stem cells migrate along radial glial

cells to their destinations

reference memory long-term memory

retinal ganglion cells neurons in the eye retina

Schwann cells glial cells of the peripheral nervous system

sensory gating the brain can adjust its responses depending on the stimulus septum inside the forebrain, associated to the basal ganglia system spatial learning spatial memory is needed to navigate around, for example

in a maze

synaptic plasticity structural or functional changes in the CNS, basis of learning and memory

synaptogenesis synapse formation

telencephalon the forebrain, is involved in higher brain functions, including movement, language, memory, learning, communication thalamus between the cerebral cortex and midbrain, is involved in

mediating spatial sense signals to the cerebral cortex ventricular and subventricular

zones

the location of proliferating neural progenitor cells in the neural tube

1.2. NEURONAL IGSF ADHESION MOLECULES AND

NMDA RECEPTORS IN DEVELOPMENT AND PLASTICITY OF THE CNS

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Fig 1. Molecular features of NCAM. (A) Schema illustrating the identifiable domains (left) and the posttranslational modifications (right) found on the NCAM protein core. (B) Molecular structure of different NCAM isoforms. As illustrated in the picture, NCAM180 and 140 are transmembrane proteins that only differ in a small portion of the intracellular domains. NCAM120 contains the extracellular domain linked to the membrane through a GPI anchor. Finally, soluble NCAM results either from an alternative splicing or from the enzymatic removal of the extracellular domain of other NCAM isoforms. (C) The current model for NCAM interactions. As depicted, NCAM cis- dimers involve the interaction between IgI and IgII (red circle). NCAM trans-interactions require the initial formation of cis-dimers. Then, two kinds of interactions between NCAM molecules on opposing cell membranes are possible (Soroka et al, 2003). The “flat zipper” interaction, illustrated in the picture, involves IgII and IgIII domains (green circle). ECD: extracellular domain;

GPI: glycosylphosphatidylinositol; ICD: intracellular domain; TMD: transmembrane domain; IgI-V:

Ig-like domain I-V; F3I/II: ﬁbronectin type 3 homology domain I/II. Reprinted from Brain Research Reviews, Gascon et al, 2007. Copyright (2007), with permission from Elsevier.

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Fig 2. An illustration of the structure of L1 and downstream signalling pathways. Different kinases are activated when L1 induces signal transduction through binding to integrins via an RGD (Arginine- Glycine-Aspartic acid) sequence in Ig domain 6. Spectrin links L1 to the actin cytoskeleton through ankyrin and L1 can also associate with microtubules (MT) via binding to doublecortin (DCX). Finally, signalling events lead to axonal outgrowth, growth cone collapse and neuronal cell migration into different areas of the brain. PI3K, phosphoinositide 3-kinase; ERK, extracellular signal-regulated kinase. Modiﬁed from Maness and Schachner, 2007.

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Fig 3. Molecular interactions and signalling of NCAM/PSA-NCAM. NCAM intrinsic signalling relies on the heterophilic interactions of the intracellular domain and mainly results in MAPK (mitogen- activated protein kinase) activation. NCAM extracellular domain interacts with a number of other proteins involved in cell adhesion, such as ECM members or other CAMs (left). Importantly, the presence of PSA (right) allows NCAM to interact with diverse signalling molecules (glutamate receptors, tyrosine kinase receptors, and p75 receptors). Since many of these new partners are able to activate intracellular signalling cascades, it has been proposed that PSA might shift NCAM activity from an anchoring to a signalling state. Reprinted from Brain Research Reviews, Gascon et al, 2007. Copyright (2007), with permission from Elsevier.

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Fig 4. Potential sites for ligand binding at NMDARs. Most NMDAR are believed to assemble as tetramers, associating two NR1 and two NR2 subunits in a ‘dimer of dimers’ quaternary architecture. For clarity, only one of the two NR1/NR2 heterodimers is shown. The extracellular region of each subunit is made up of a tandem of ‘Venus-ﬂytrap’ domains, the N-terminal domain (NTD) and the agonist-binding domain (ABD). In the extracellular region, the subunits dimerize at the level of the ABDs and probably also at the level of the NTDs. The NR2 ABD binds glutamate, whereas the NR1 ABD binds the coagonist glycine (or D-serine). White arrows indicate binding sites for competitive agonists and antagonists. Thick orange arrows indicate sites known to bind allosteric modulators such as endogenous zinc (NR2A and NR2B NTDs) or ifenprodil-like compounds (NR2B NTDs), both acting as non-competitive antagonists.. The ion-channel domain also forms binding sites for pore blockers such as endogenous Mg2+, MK-801, memantine or ketamine, acting as uncompetitive antagonists. Thin orange arrows indicate putative modulatory sites, which can bind either positive or negative allosteric modulators. The only known NMDAR antagonists that display strong subunit selectivity are the NR2 NTD ligands Zn2+, which selectively inhibits NR2A-containing receptors at nanomolar concentrations, and ifenprodil-like compounds , which selectively inhibit NR2B-containing receptors. Reprinted from Current Opinion in Pharmacology, Paoletti and Neyton, 2007. Copyright (2007), with permission from Elsevier.

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Fig 5. The NMDA receptor scaffolding complex in the synaptic junction. NR2 subunit binds to PSD-95 and D-actinin in the cytoplasm. Signalling molecules. such as Src, PKA and the synaptic Ras GTPase- activating protein (SynGAP) localize with the NMDAR. Calmodulin (CaM) and many other proteins, including D-actinin bind to the NR1 subunit. PM, plasma membrane. Modiﬁed from Waxman and Lynch, 2005.

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Fig 6. Structure of dendritic ﬁlopodia and spines, and a model of an asymmetric synapse. (A) Filopodia are the precursors of dendritic spines, and they develop into three types of dendritic spines: thin type, stubby type and mushroom type spines. Gray disks: PSD structure and red circles: F-actin.

(B) The synapse is formed between the presynaptic terminal and the dendritic spine. Synaptic vesicles are found in the presynaptic terminal. Two structural elements: actin cytoskeleton and PSD are important for the function of the dendritic spine. PSD contains the neurotransmitter receptors.

Actin-binding proteins, including drebrin, are stabilizing the dendritic spine architecture. Modiﬁed from Sekino et al, 2007.

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Fig 7. A schematic illustration of Į-actinin in its native form. Each monomer contains an N-terminal actin-binding domain (AB) consisting of two calponin-homology domains, a central rod domain region with four D-helical spectrin-like repeats (R1-R4), and a C-terminal CaM domain consisting of four Ca²⁺-binding EF-hand repeats. Modiﬁed from Sjoblom et al, 2008.

3.3. INTERACTIONS

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The neuronal cell adhesion molecule ICAM-5