The concept of synaptopathy refers to any brain disorder related with the impairment of synaptic junctions. Indeed, this definition does not really distinguish whether synaptic dysfunction is the cause or the consequence of such disorders, and often knowing where and when the onset of a disease occurs it is not clear. What is clear is that synapses dysfunctions are involved in many neurodevelopmental and neurodegenerative diseases, sometimes at the early stages.
Synapses are neuron components that make flow the information in the brain. They are responsible for the neurotransmission of excitatory or inhibitory signals, via glutamate or glycine/gamma-aminobutyric acid (GABA) respectively, and their modulation permits the maintenance of brain homeostasis. Alterations in synapses functionality, even in a slight – but enduring – way, can often lead to brain disorders.
The main goal of the study presented in this article is to outline the complexity of the interactions in the pre- and post-synaptic compartments, and to describe the components with have a role in synaptopathies.
Without entering in details, it can be said that the pre-synaptic compartment has the same structure in both excitatory and inhibitory synapses. Neurotransmitters stored in vesicles are released in the synaptic cleft in response to the depolarization of the pre-synaptic membrane. This process depends on Ca++ levels and on many regulatory and structural proteins acting in a coordinated network. Just some protein names: synaptogamin I, SNARE complex, Rab3a interacting molecule, and so on.
Post-synaptic compartment shows some structural and molecular differences depending on its excitatory or inhibitory behavior. Main protein groups in the excitatory pathway are the ProSAP/Shank family, ionotropic glutamate receptors (iGluRs) such as AMPARs y NMDARs, and metabotropic glutamate receptors (mGluRs). Inhibitory post-synaptic compartment contains, among others, gephyrin, collybistin, GABAA and GABAB receptors, and glycine receptors (GlyRs).
All the mentioned proteins have a role in one or more brain disorders, hereafter divided in two groups.
Neurodevelopmental disorders
Autism spectrum disorders are a large group of disorders caused by more than 600 genetic variants, many of them affecting synaptic protein genes. For example, mGluRs are overexpressed in Fragile X syndrome patients, probably due to the lack of another protein (FMRP) that normally limits mGluRs translation. NMDAR under- or over-expression leads in both cases to autism behavior in mice, thus revealing the refined regulation of the whole system.
Down syndrome (DS), caused by a supplementary copy of chromosome 21 in humans, shows a lack of regulation of the endocytosis mechanism, and an excess of GABA release. A change in the expression of various regulatory proteins leads to the malfunction at synaptic level. Unfortunately, mice models used in DS studies are not really reliable for understanding the basic molecular mechanisms in humans.
Mutations in GlyRs cause the alteration of glycinergic signaling pathway, thus leading to the development of hyperekplexia (also called Startle Disease). The main characteristics of hyperekplexia are the amplification of the normal startle reflex, and stiffness at birth and after a startle.
Epilepsy is very common in children and as a rule is caused by the increase of glutamatergic transmission and the decrease of GABA releasing. Epilepsy can start after a trauma, such as a stroke or a brain injury, or may have a genetic origin. In this case, synaptic proteins, sodium channels, and neurotransmitter transporters are affected, and synapses lose their normal morphology and function.
Neurodegenerative diseases
Alzheimer disease is caused by the accumulation of the amyloid beta (Ab) peptide – known as amyloid plaques – in the extracellular space of brain cells, and by the aggregation of tau protein into the cells. However, studies in transgenic mice have shown that Ab soluble oligomers also have another role: they interact with a lot of synaptic proteins, such as mGluRs, iGluRs, and prion protein, that activate NMDARs in an abnormal way. The result is the impairment of synapses and the onset of memory loss before the onset of the amyloid plaques.
The impairment of dopamine metabolism is a trait of the Parkinson disease (PD). Although most of PD cases are idiopathic, i.e. of unknown origin, some genetic mutations related with PD have been found. In these cases, synaptic proteins SNARE are affected, but basic molecular mechanisms are not clarified yet.
Different pediatric neurodegenerative disorders are related to synaptic dysfunction, in particular diseases in which cellular trafficking is impaired.
MAIN MESSAGES
The impairment of a single component of the complex molecular machinery at the synaptic level can affect the synapse function, and may lead to the development of neurological diseases. They can be both developmental and neurodegenerative disorders. Synaptopathies are brain disorders related with the impairment of synaptic junctions. Synaptic proteins altered by genetic causes can be a potential target for new therapeutic approaches.
Reference:
Lepeta K. et al. Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students. J. Neurochem. (2016) 138, 785-805
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).
