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| Shank3 synapse |
Shank3 is a scaffolding protein involved in neuronal connections, formation and maturation of dendritic spines. Shank3 postsynaptic protein with the associated glutamate receptors function together to form spines and functional synapses [1] [2]. It's mutation has been implicated in neurobehavioral symptoms in autistic individuals. Some of the evidence showing that shank3 mutation can be identified in autistic individuals is provided by mice models, a disruption of shank3 in generated knockout mice shows causality between a disruption in the shank3 gene and the genesis of autistic-like behaviours [2]. Both structural and functional neuroimaging have shown alerted neuronal connectivity in various brain areas; for instance, in areas that function to accomplish language problems, such as the left inferior frontal gyrus and temporal gyrus. It is believed that understanding the molecular dynamics of shank3 translates into targeted pharmacological treatments for shank3 mutation and thus treatment of autism [2]. Presently studies that have dealt with molecular intervention in knockout mice have been successful in reversing some autistic symptoms.
1.1 Shank3 Presynaptic effects
Shank3 gene is located on chromosome 22, it is also known as ProSAP2. It regulates the structural organisation of dendritic spines and is a binding partner of neuroligin-neurexin complex. Shank3 is a strong candidate gene for autism characterised by abnormal brain development. Durand et al research findings report that a mutation of a single copy of Shank3 on chromosome 22q13 results in social communication disorder. Behaviourally, mutant mice show increased anxiety-related behaviour and impaired contextual fear memory, suggesting the importance of Shank3 for synapse structure[1]. Considering the involvement of Shank3 in dendritic spine formation and it binding to neuroligin, it is evident that shank3 plays an important role in the etiology of autism.
1.1.a Neuroligin and Neurexin
Neuroligins and neurexins are synaptic proteins that function to mediate the formation of synapses between neurons, pre- and postsynaptic signaling, and to facilitate neural networks to process complex signal[3]. Neurexins and neuroligins are located presynaptically and postsynaptically respectively. Neurexins bind neuroligins across the synaptic cleft, in turn neuroligin bind to the PSD95 proteins that then interact with SAPAP and Shank proteins. Neurexin-Neuroligin complex is critical for synaptic formation. The disruption of the normal molecular machinery of neuroligins and neurexins is implicated in autism[4]. The discovery of deletions in the Xp22.1 region in three individual diagnosed with autism lead to the suggestion that neuroligin is connected to autism. Jamain et al examined this region and found mutations in NLGN4X, which plays role in the identification of inhibitory versus excitatory synapses, in several cases of autism, but not in the controls[9] Subsequent studies conducted have found that disruption of neuroligin suppress its affinity to its receptor neurexin and decreases its accumulation in postsynaptic membrane. In addition, mutations seen in Neuroligin have been modeled in mice. Mice with an amino acid change that replicates the protein encoded by the neuroligin gene in humans exhibit impaired social interaction and social deficits[10] . Various experiments conducted have shown the critical importance of neurexin-neuroligin linkage. Targeted disruption of either of the genes in mice results in synaptic transmission drawbacks and inhibited social communication[6]. Considered together, these studies in mice strongly link autism with the malfunction of neurexin and neuroligin. copy-number-variations
1.1.b ProSAP/ Shank family
ProSAP/Shank are scaffolding molecules that interact with receptors located postsynaptically, these include NMDA-type and mGluR and the actin-based cytoskeleton. ProSAP/Shank proteins mainly function to modulate synaptic plasticity, which research has shown to be crucial for learning and memory[6]. The dysregulation of ProSAP/Shank among autistic individual lead to the speculation of a link between ProSAP/Shank and autism. Research found that a disruption of ProSAP/Shank lead to the loss of synaptic stability, immature synapse morphology and an imbalance between excitation and inhibition [6]. Furthermore, studies that have looked at the disruption of ProSAP/Shank gene in mice have observed an exhibition of fewer dendritic spines and decreased synaptic transmission. Mutant mice display hyperactivity and autistic like behaviors such as excessive grooming and abnormal social behaviors[8]. These scaffolding proteins are also crucial in glutamatergic synaptic signaling, including ionotropic and metabotropic glutamate receptor-mediated transmission through the interaction with Homer and the GKAP/PSD-95 protein complex. Shank codes for several postsynaptic scaffolding proteins that interact with neuroligins. Diminished Shank protein function has been implicated in 22q13.3 deletion syndrome which is characterized by autistic like behaviors.
(Durand et al, 2011).
1.2 Glutamatergic signaling pathway disruption
Shank3 gene is located on chromosome 22, it is also known as ProSAP2[13]. It regulates the structural organisation of dendritic spines and is a binding partner of neuroligin-neurexin complex[13][15]. Shank3 is a strong candidate gene for autism characterised by abnormal brain development. Durand et al research findings report that a mutation of a single copy of Shank3 on chromosome 22q13 results in social communication disorder[16]. Behaviourally, mutant mice show increased anxiety-related behaviour and impaired contextual fear memory, suggesting the importance of Shank3 for synapse structure [1].molecular-mechanisms-of-schizophrenia Considering the involvement of Shank3 in dendritic spine formation and it binding to neuroligin, it is evident that shank3 plays an important role in the etiology of autism.
1.3 Dendritic spine alterations
Shank 3 mutations in autistic individuals leads to modification of dendritic spine. Bourgeron and colleagues study provides insight into the contribution of shank3 gene mutation to the actin-dependent formation of dendritic spines[12]. The overexpression of different constructs in hippocampal neurons facilitated the examination of postsynaptic spines organisation and shape. The analysis of sub-cellular localization of different shank3 mutants co-transfected with an RFP plasmid resulted in the accumulation protein in dendritic spine. Furthermore the data from the study suggests an increment in F-actin levels which translate into enlarged dendritic spines[14]. The study made use of cortactin which is a binding protein for F-actin, it is mainly found in the cell matrix contact sites that mediate the nucleation of new actin filaments. Furthermore, shank3 binding to cortactin and the loss of cortactin caused decreased spine density[14].
1.4 Brain mapping in autism
Attempts at uncovering the neuroanatomical abnormalities that underlie neurobehavioral deficit in autism have been proven rather difficult to establish reliably[3]. However, the common consensus is that autism probably affects the brain widely, because it involves developmental abnormalities of motor, sensory and cognitive functions and social communication. Both structural and functional magnetic resonance imaging show various specific areas of maldevelopment[23]. Studies conducted amongst the general population reported the changes in the prefrontal cortex, medial and ventral temporal lobe, superior temporal sulcus, amygdala and cerebellum[19]. immune-dysregulation-and-autism In addition, core prefrontal–striato-parietal grey matter abnormalities in autism may be replicable in age-matched and intellectually able groups, using automated voxel-based whole brain analysis methods.
Image shows grey matter deficit in autism. Deficit in grey matter volume
In autistic children versus control. ( McAlonan et al, 2004).
1.5 Therapeutic interventions
Attempts at uncovering the neuroanatomical abnormalities that underlie neurobehavioral deficit in autism have been proven rather difficult to establish reliably[20][23]. However, the common consensus is that autism probably affects the brain widely, because it involves developmental abnormalities of motor, sensory and cognitive functions and social communication[13]. Both structural and functional magnetic resonance imaging show various specific areas of maldevelopment. Studies conducted amongst the general population reported the changes in the prefrontal cortex, medial and ventral temporal lobe, superior temporal sulcus, amygdala and cerebellum [19]. In addition, core prefrontal–striato-parietal grey matter abnormalities in autism may be replicable in age-matched and intellectually able groups, using automated voxel-based whole brain analysis methods[22] . autism-treatments
Great information Beza! I linked to you for the information on neurexins and neuroligins, I hope that's okay :) Also, make sure you cite everything, it looks like there might be some citations missing for section 1.2 and 1.4. Don't forget to link up with other pages! :)
Will do Stephanie, thank you so much for the feedback.
copy number variations