Neurexin

Neurexins (NRXN) are a family of presynaptic

In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1–3) and beta-neurexins 1-3 (β-neurexins 1–3).^[6] In addition, there are alternative splicing at 5 sites in α-neurexin and 2 in β-neurexin; more than 2000 splice variants are possible, suggesting its role in determining synapse specificity.^[7]

The encoded proteins are structurally similar to

Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts.[2] This region surrounds a coordinated Ca²⁺ ion and is the site of neuroligin binding,^[10] resulting in a neurexin-neuroligin Ca²⁺-dependent complex at the junction of chemical synapses.^[11]

Expression and function

Neurexins are diffusely distributed in neurons and become concentrated at presynaptic terminals as neurons mature. They have also been found at

The different combinations of neurexin to neuroligin, and alternative splicing of neuroligin and neurexin genes, control binding between neuroligins and neurexins, adding to synapse specificity.^[8] Neurexins alone are capable of recruiting neuroligins in postsynaptic cells to a dendritic surface, resulting in clustered neurotransmitter receptors and other postsynaptic proteins and machinery. Their neuroligin partners can induce presynaptic terminals by recruiting neurexins. Synapse formation can therefore be triggered in either direction by these proteins.^[10] Neuroligins and neurexins can also regulate formation of glutamatergic (excitatory) synapses, and GABAergic (inhibitory) contacts using a neuroligin link. Regulating these contacts suggests neurexin-neuroligin binding could balance synaptic input,^[7] or maintain an optimal ratio of excitatory to inhibitory contacts.

Additional interacting partners

Dystroglycans

Neurexins not only bind to neuroligin. Additional binding partners of neurexin are dystroglycan.^[10] Dystroglycan is Ca²⁺-dependent and binds preferentially to α-neurexins on LNS domains that lack splice inserts. In mice, a deletion of dystroglycan causes long-term potentiation impairment and developmental abnormalities similar to muscular dystrophy; however baseline synaptic transmission is normal.

Neuroexophilins

Neuroexophilins are also known to bind to neurexins and are present at the synaptic cleft but are not membrane bound.^[10][13] Neuroexophilins are Ca²⁺-independent and bind exclusively to α-neurexins on the second LNS domain. The increased startle responses and impaired motor coordination of neuroexophilin knockout mice indicates that neuroexophilins have a functional role in certain circuits.^[10]

Latrophilins

Latrophilins are adhesion G protein-coupled receptors that reside on the postsynaptic membrane.^[13] Without latrophillins in mice a loss of excitatory synapses was experienced in pyramidal neurons.^[14] Latrophillins while in association with neurexin have been shown to act as postsynaptic recognition molecules for incoming axons.^[13]

Cerebellins

Cerebellins are small proteins that are secreted into the synaptic cleft where they associate with other cerebellins to form a

C1Q1's structure is similar to that of cerebellin as it is a small protein that is secreted that associates with multiple copies of itself.[13] C1q1 while in the synaptic cleft binds neurexin on the presynaptic side and BAI3 which is another adhesion G protein-coupled receptor. The deletion of c1q1 causes the loss of climbing fibers and excitatory signaling in general.^[19] C1q1s are found broadly throughout the brain including the prefrontal cortex, amygdala, cerebellum, and potentially more.^[20]

Species distribution

Members of the neurexin family are found across all animals, including basal metazoans such as

Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia.[12] In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler.^[6] Their functional roles in insects are likely similar to those in vertebrates.^[21]

Role in synaptic maturation

Neurexin and neuroligin have been found to be active in synapse maturation and adaptation of synaptic strength. Studies in knockout mice show that the trans-synaptic binding team does not increase the number of synaptic sites, but rather increases the strength of the existing synapses.^[12] Deletion of the neurexin genes in the mice significantly impaired synaptic function, but did not alter synaptic structure. This is attributed to the impairment of specific voltage gated ion channels. While neuroligin and neurexin are not required for synaptic formation, they are essential components for proper function.^[12]

Clinical importance and applications

Recent studies link mutations in genes encoding neurexin and neuroligin to a spectrum of cognitive disorders, such as

Autism

Autism is a

Similar to schizophrenia, studies have shown that intellectual disability and Tourette syndrome are also associated with NRXN1 deletions.^[5][26] A recent study shows that NRXN genes 1-3 are essential for survival and play a pivotal and overlapping role with each other in neurodevelopment. These genes have been directly disrupted in Tourette syndrome by independent genomic rearrangements.^[29] Another study suggests that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms.^[30]

See also

• Cell adhesion molecule
• Synaptogenesis

References