**6. Cytoskeletal dynamics**

proteins rich in leucine (LRRTMs), N-cadherin/β-catenin, ephrins and Eph, SynCAM receptors

The Nrxs and NLS contain an extracellular domain that participates in the pre and postsynaptic interaction and an intracellular domain that is involved in multiple functional interactions and regulatory processes. They interact with high affinity via their extracellular regions [135, 136]. Nrxs create extracellular protein-protein interactions with the intracellular signaling cascade. NLS binds to areas of postsynaptic density (PSD), proteins which are supported by glutama‐ tergic synapses. In postsynaptic sites, the NLS/Nrxs interactions cause an increase in the PSD agglomeration recruitment of postsynaptic N-methyl-D-aspartate (NMDA) and α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Thus, the binding of Nrxs and NLS helps to align presynaptic and postsynaptic receptor release (Budreck et al., 2013; Mondin,

LRRTMproteins are a groupoftype Itransmembraneproteins containing extracellularleucinerich repeats and a short cytoplasmic tail. They play a key role in the development and matura‐ tion of synapses, but are also directly involved in synaptic transmission and more complex behavior [87]. Contactins (CNTNs) provide a set of glycan phosphatidyl-inositol (GPI) Ig-CAM links containing six N-terminal Ig-like domains and four Fibronectin Type III domains. CNTNs play an important role in the formation of axon connections in the developing nervous system. For example, Cntn-1 and Cntn-2 are involvedin axon growth andguidance, and Cntn-6

As most neurological diseases originate as a dysfunction of neural circuits whose function is highly dependent on the accuracy of cell-cell adhesions, there is increasing evidence connect‐ ing several neurological disorders with mutations or altered expressions of CAMs. For example, mutations in the *NLS* and *Nrxs* genes are found in patients with autism [136]. Therefore, research on the role of CAMs will help provide a better understanding of the

Alterations in neurotransmission and its components, such as synaptic vesicles seem to be one of the keys in neurological disorders. Abnormalities in synaptic vesicle endocytosis and recycling may contribute with this type of disorder. Exoendocytic cycling of synaptic vesicles, which are organelles of 40 nm in diameter, is involved in neurotransmitter release. Hundreds of synaptic vesicles, filled with neurotransmitters are found in each presynaptic nerve terminal. When presynaptic plasma membranes depolarize, Ca2þ-channels open and calcium flows into the nerve terminal, triggering the exocytosis of synaptic vesicles and releasing their neurotransmitters into the synaptic cleft. Calcium binds to synaptotagmin, and after exocyto‐ sis, vesicles are re-endocytosed, recycled, and refilled with neurotransmitters. Recycling can occur by multiple parallel pathways, either by fast recycling via local reuse of vesicles, or by slower recycling through an intermediate endosomal [137]. Also, a critical step in presynaptic differentiation is the clustering of synaptic vesicles near neurotransmitter release sites, the active zone, where vesicle fusion and exocytosis of neurotransmitters occur. Synaptic vesicles

is expressed in the presynaptic region in the developing nervous system [169].

underlying mechanisms of pathogenic neurological disorders [172].

and integrins [161].

320 Autism Spectrum Disorder - Recent Advances

Tessier, Thoumine, 2013).

**5. Synaptic vesicles**

The cytoskeleton forms the backbone of neuronal architecture and is essential for axon growth and synapse formation. The microtubule cytoskeleton has an active role during different phases of neuronal polarization; microtubules and their stability determine axon formation, they maintain the identity of axons and they regulate the dynamics of dendritic spines. Once the synapses have been formed, the neuronal cytoskeleton supports maturation and mainte‐ nance, and so the synaptic cytoskeleton is essential for the stabilization and remodeling of synaptic connections [40]. Actin filaments are the predominant component of the cytoskeleton in dendritic spines [20]. Changes in these key molecules mediating that bind to actin and members of the Rho family of small GTPases, such as RhoA, Rac and Cdc42 can disrupt this process [69]. These proteins play important roles in synaptic functions, dendritic branching, the formation and maintenance of dendritic spines and the growth and differentiation of neurites [133]. Their genes include *OPHN1, MEGAP, OCRL1, ARHGEF6, ARHGEF9, FGD1, LIMK1, PAK3*, and *IQSEC2* [133].

It is known that genetic alterations in the pathways controlling local protein synthesis in neurons contribute to diverse intellectual disabilities and ASD. A set of cytoskeletal proteins has been reported as mutated in these individuals. The resulting disorders are called synap‐ topathies with dysgenesis of dendritic spines being a recurrent anatomical feature. These include factors that regulate the dynamics of the actin cytoskeleton, such as GAPs and guanosine factors [12]. Mutations in the tumor suppressor genes, *TSC1* and *TSC2*, are also connected to the ASD mutant proteins that seem to disturb the dynamics of the cytoskeleton and the structure of dendritic spines [61]. Moreover, the microtubule-associated protein, *KATNAL2*, has emerged as a risk factor for ASD [105]. But the best example of dendritic spine defects is Fragile X syndrome. This disease results from a loss of function of the RNA-binding protein, the fragile X mental retardation protein (FMRP), which regulates dendritic targeting of mRNAs and controls protein synthesis and mRNA decay in neuronal soma and at synapses. High-throughput screenings have revealed that a wide array of neuronal mRNAs is targeted by FMRP, suggesting that simultaneous dysregulation of many proteins contributes to the syndrome, including cytoplasmic FMRP-interacting protein 1 (CYFIP1) [38].

New research has revealed many interactions associated with brain disorders, opening up new perspectives to define regulatory pathways shared by neurological disabilities characterized by dendritic spine dysmorphogenesis.
