Abstract
The progress of developing effective interventions against psychiatric disorders has been limited due to a lack of understanding of the underlying cellular and functional mechanisms. Recent research findings focused on exploring novel causes of psychiatric disorders have highlighted the importance of the axonal initial segment (AIS), a highly specialized neuronal structure critical for spike initiation of the action potential. In particular, the role of voltage-gated sodium channels, and their interactions with other protein partners in a tightly regulated macromolecular complex has been emphasized as a key component in the regulation of neuronal excitability. Deficits and excesses of excitability have been linked to the pathogenesis of brain disorders. Identification of the factors and regulatory pathways involved in proper AIS function, or its disruption, can lead to the development of novel interventions that target these mechanistic interactions, increasing treatment efficacy while reducing deleterious off-target effects for psychiatric disorders.
Highlights
DISORDERS OF THE BRAIN The human brain is known for its incredible complexity and heterogeneity
Current widely used treatments against psychiatric disorders are fraught with mixed efficacy, poor patient tolerability, and high rates of relapse
As demonstrated in the clinical antipsychotic trials of intervention effectiveness (CATIE) study [7], even current effective frontline treatments for disorders such as schizophrenia come with a myriad of side effects
Summary
Dravet syndrome (severe myoclonic epilepsy of infancy) [83, 86] Sporadic autism and familial autism [92] Autism spectrum disorders [93] Familial hemiplegic migraine [95] Mesial temporal sclerosis [96] Possibly linked to Dravet syndrome [86] Ohtahara syndrome (infantile epileptic encephalopathy) [89] Autism spectrum disorders [92] Bipolar disorder [16, 97, 98] Schizophrenia [99, 101,102,103] Post-traumatic stress disorder [99] Late-onset Alzheimer’s disease [104] Aging and Alzheimer’s [108, 109] West syndrome (infantile spasm) [112] Spinocerebellar ataxia type 5 [160] Combined spherocytosis and autism [106] Auditory and motor neuropathies [107] Multiple sclerosis [116,117,118] Central and peripheral demyelination disorder [116,117,118] Schizophrenia [120] Mental retardation [122,123,124] Spinocerebellar ataxia type 27 [50, 130, 131] Paroxysmal dystonia [137] Cognitive impairment [138] Major depressive disorder [133]. Through the engineering of small molecules or peptidomimetics [144, 145] that interact with and disrupt specific protein–protein interfaces, the effects of the inhibitor on the signaling network of the cell would be restricted from n edges (n = number of potential PPI between the targeted protein and the entire proteome) to a single edge. Interaction of the serotonin 5HT2C receptor with multiple PDZ (MPDZ), a gene found to be dysregulated in physiological drug dependence [158], has been explored as a potential avenue of research in addiction phenotypes, and small molecule inhibitors of the MPDZ–5HT2C interaction have been developed [159] These early successes highlight the potential for harnessing PPI at the AIS as a novel approach toward better interventions against psychiatric disorders. Through the engineering of novel therapeutics that target dysregulation at the interaction level, versus the protein level, there is much potential for greater specificity and diversity in the design of useful psychiatric treatments
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