Synaptic Plasticity, Metaplasticity and Depression

Abstract

The development of a persistent depressive affective state has for some time been thought to result from persistent alterations in neurotransmitter-mediated synaptic transmission. While the identity of those transmitters has changed over the years, the literature has lacked mechanistic connections between the neurophysiological mechanisms they regulate, and how these mechanisms alter neuronal function, and, hence, affective homeostasis. This review will examine recent work that suggests that both long-term activity-dependent changes in synaptic strength (“plasticity”), and shifting set points for the ease of induction of future long-term changes (“metaplasticity”), may be critical to establishing and reversing a depressive behavioral state. Activity-dependent long-term synaptic plasticity involves both strengthening and weakening of synaptic connections associated with a dizzying array of neurochemical alterations that include synaptic insertion and removal of a number of subtypes of AMPA, NMDA and metabotropic glutamate receptors, changes in presynaptic glutamate release, and structural changes in dendritic spines. Cellular mechanisms of metaplasticity are far less well understood. Here, we will review the growing evidence that long-term synaptic changes in glutamatergic transmission, in brain regions that regulate mood, are key determinants of affective homeostasis and therapeutic targets with immense potential for drug development.

From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder

“…These functions may be achieved through actions on NMDA and metabtropic glutamate receptors (mGluRs) or heterosynaptic metaplasticity mechanisms like synaptic tagging and capture (Abraham, 2008 ; Hulme et al, 2013 ). Metaplasticity is sensitive to environmental stimuli, like environment enrichment or stress and dysregulation of metaplasticity induced by chronic stress may contribute to induction of depression (Vose and Stanton, 2017 ). For a detailed description of mechanisms underlying metaplasticity and their clinical relevance, the impressive articles of Abraham and Bear ( 1996 ), Abraham ( 2008 ) and Hulme et al ( 2013 ) may be valuable.…”

The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

“…Indeed, ARC is an early onset gene with an important role in neuroplasticity (Li et al, 2015;Peebles et al, 2010). Alteration of its function may concur to the development of more frail (inefficient) neuronal microenvironment (less dendritic spines) which in turn may alter normal behavior (Vigers et al, 2012;Vose & Stanton, 2017).…”

The Long Run: Neuroprotective Effects of Physical Exercise on Adult Neurogenesis from Youth to Old Age

“…In fact, adult neurogenesis is altered following stress paradigms in rodents [ 118 ]. It has been hypothesized that, in major depression, the brain may be unable to respond to stressful stimuli with appropriate adaptive plasticity [ 119 ] – and impaired neurogenesis may represent one factor contributing to such a reduction of plasticity. The “neurogenesis hypothesis” of depression came from research carried out in rodent stress models.…”