Synaptic alterations associated with depression and schizophrenia: potential as a therapeutic target

ABSTRACT

Introduction: In recent years, the concept of ‘synaptopathy’ has been extended from neurodegenerative and neurological disorders to psychiatric diseases. According to this nascent line of research, disruption in synaptic structure and function acts as the main determinant of mental illness. Therefore, molecular systems and processes crucial for synaptic activity may represent promising therapeutic targets.

Areas covered: We review data on synaptic structural alterations in depression and schizophrenia and on specific molecular systems and/or mechanisms important for the maintenance of proper synaptic function. Specifically, we examine the involvement of the neuroligin system, the local protein translation, and the neurotrophin BDNF by reviewing clinical and preclinical studies, with particular attention to results provided by using animal models based on the role of stress in psychiatric diseases. Finally, we also discuss the impact of pharmacological treatment on these molecular systems/mechanisms.

Expert opinion: The relevance of synaptic dysfunctions in psychiatric diseases is undoubted and the potential to normalize, ameliorate, and shape such alterations by acting on molecular systems crucial to ensure synaptic function property is fascinating. However, future studies are required to elucidate several open issues.

KEYWORDS:

• Synapse
• depression
• schizophrenia
• stress
• structural abnormalities
• neuroligins
• mTOR
• brain-derived neurotrophic factor

Article highlights

• Psychiatric diseases, such as depression and schizophrenia, are characterized by synaptic dysfunctions at both structural and molecular levels and may therefore be considered as ‘synaptopathies’.

• At the structural level, depression and schizophrenia are both characterized by reduced volume of specific brain regions, loss of spines, and alteration in dendritic arborization.

• Synaptic alteration of molecular systems with a key role in the maintenance of the function of the synapse, such as NLGNs, mTOR, and BDNF, may contribute to the observed structural dysfunctions and may be important targets for pharmacological interventions.

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Declaration of interest

MA Riva has received compensation as speaker/consultant from Eli Lilly, Otzuka, Servier, Sumitomo Dainippon Pharma, Sunovion, and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.