Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students

Abstract

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Keywords: Alzheimer disease; Down syndrome; autism; epilepsy; hyperekplexia; synapses.

Figure 1

Schematic overview of excitatory synapse‐linked disease mechanisms. Functional overview of the excitatory synapse with main proteins and pathways affected in autism spectrum disorders (ASD), Alzheimer disease (AD), and Parkinson disease (PD). Proteins and pathways are color coded for each disorder (ASD – blue; AD – green; PD – red). Dashed line divides the pre‐synaptic part into dopaminergic and glutamatergic terminals. ROS – reactive oxygen species. Altered (either increased or decreased) function of NMDA and AMPA receptors, disrupted mGluR signaling and consequently changes in long‐term depression (LTD) are postulated to play a crucial role in the development of ASD. Such mechanisms likely culminate in altered protein synthesis at the post‐synapse. Notably, FMRP deficiency results in elevated translation and autism‐like behaviors in FXS. In AD, the post‐synaptic action of Aβ oligomers and tau aggregates result in deregulation of NMDA receptors (NMDARs), cellular stress, and decreased protein synthesis. Aβ oligomers further act through interactions with neuroligin‐1 and mGluR5 to impair neuronal homeostasis. Pre‐synaptic disturbances, including impaired BDNF transport and excessive D‐serine production, have also been associated with AD. Such abnormal molecular cascades ultimately result in defective LTP and memory. In PD, defective autophagy and α‐synuclein‐mediated mislocalization of SNARE complexes associate with decreased DA release and mitochondrial function. This leads to increases in oxidative stress, likely driving impaired dopaminergic tonus and neuronal death that are characteristic of PD.

Figure 2

Schematic overview of inhibitory synapse‐linked disease mechanisms. Functional overview on the inhibitory synapse with main proteins and pathways affected in hyperekplexia, Down syndrome (DS), and epilepsy. Proteins and pathways are color coded for each disorder (hyperekplexia – orange; DS – blue; epilepsy – purple). Dashed line divides the scheme into glycinergic and GABAergic synapse. The major cause of hyperekplexia is defective glycinergic signaling resulting from mutations in genes involving subunits of GlyRs, glycine transporter, or GlyR‐interacting proteins. Excitation–inhibition imbalance underlies deficient synapse function in epilepsy and DS. In epilepsy, abnormal excitatory tonus results from decreased GABA release and concurrent enhanced glutamatergic neurotransmission. In DS, an over‐inhibition of synapses by increased GABAergic circuitry and endocytic dysfunction is considered the main synaptic hallmark of the disease.