Synaptic plasticity and mental health: methods, challenges and opportunities

Abstract

Activity-dependent synaptic plasticity is a ubiquitous property of the nervous system that allows neurons to communicate and change their connections as a function of past experiences. Through reweighting of synaptic strengths, the nervous system can remodel itself, giving rise to durable memories that create the biological basis for mental function. In healthy individuals, synaptic plasticity undergoes characteristic developmental and aging trajectories. Dysfunctional plasticity, in turn, underlies a wide spectrum of neuropsychiatric disorders including depression, schizophrenia, addiction, and posttraumatic stress disorder. From a mechanistic standpoint, synaptic plasticity spans the gamut of spatial and temporal scales, from microseconds to the lifespan, from microns to the entire nervous system. With the numbers and strengths of synapses changing on such wide scales, there is an important need to develop measurement techniques with complimentary sensitivities and a growing number of approaches are now being harnessed for this purpose. Through hemodynamic measures, structural and tracer imaging, and noninvasive neuromodulation, it is possible to image structural and functional changes that underlie synaptic plasticity and associated behavioral learning. Here we review the mechanisms of neural plasticity and the historical and future trends in techniques that allow imaging of synaptic changes that accompany psychiatric disorders, highlighting emerging therapeutics and the challenges and opportunities accompanying this burgeoning area of study.

Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

“…We took advantage of the HuDis-TRiP fly RNAi collection, which contains 92% coverage of the highest-confidence fly ortholog of human disease genes ( 22 ). Given that altered synaptic plasticity is associated with numerous neurological disorders ( 5, 6 ), we focused the screen on genes affecting nervous system functions in human when mutated. We examined genes that differentially affect (1) synapse development and (2) activity-induced synaptic remodeling using RNAi-based approach, which allows the uncoupling of the two processes to identify genes most sensitive to perturbation and therefore important for each respective process.…”

“…Such activity-induced synaptic remodeling has been observed in diverse organisms, and shown to be important for behavior, cognition, and learning (2)(3)(4). Consequently, defective synaptic plasticity has been linked to numerous neurological disorders (5,6).…”

“…Such activity-induced synaptic remodeling has been observed in diverse organisms, and shown to be important for behavior, cognition, and learning ( 2–4 ). Consequently, defective synaptic plasticity has been linked to numerous neurological disorders ( 5, 6 ). Studies have revealed that synaptic development and synaptic plasticity are intertwined ( 7–9 ), therefore making it particularly challenging to identify the molecular and cellular pathways required for activity-induced synaptic remodeling without complications from abnormal synapse development.…”

Low and high dose methamphetamine differentially regulate synaptic structural plasticity in cortex and hippocampus

“…The Rac1 is known to activate multiple signaling pathways which could regulate synaptic remodeling through actin branching ( Rouiller et al, 2008 ; Firat-Karalar and Welch, 2011 ). Moreover, Rac1 activation is associated with the decay of hippocampus-dependent spatial memory in mice and olfactory memory in flies ( Wu et al, 2019 ), and learning and memory rely on synapse-specific modifications ( Appelbaum et al, 2022 ). Rac1 inhibition rescued memory loss in AD mice ( Wu et al, 2019 ).…”

Epigenetic signature in neural plasticity: the journey so far and journey ahead

“…Thus, studying synaptic and neural plasticity is very important to underpin the cellular and molecular mechanisms regulating plasticity in the nervous system. By understanding the mechanism of neural plasticity and associated dynamics involved in this mechanism the synaptic dysregulation can be controlled with an appropriate intervention [ 12 ]. Recently, epigenetic processes within the brain were investigated because of their acknowledged implications in basic biology, psychology, and neuropharmacology.…”