Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Abstract

Summary:Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

“…Thus, increases in synaptic strength are considered to underlie the increases in MEP amplitude (Thickbroom et al, 2006). Although there is limited and indirect knowledge of the processes underlying associative LTP in humans, it is believed to involve glutamate signaling and postsynaptic cell depolarization through N-methyl-Daspartate (NMDA) and a-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) receptor activation (Pittenger and Duman, 2008), which are each enhanced by BDNF (Carlson et al, 2006). Glutamate acts synergistically with BDNF and tyrosine-related kinase B (TrkB) signaling to increase NMDA activity and AMPA receptor expression (Yoshii and Constantine-Paton, 2010), both of which result in greater intracellular calcium influx.…”

“…The neurobiology of major depressive disorder (MDD) includes evidence for altered cortical activity (Savits and Drevets, 2009), shrinkage of neurons and glial cells, loss of dendritic complexity in the hippocampus and prefrontal cortex (PFC) (Kanner, 2004;Carlson et al, 2006), and lower levels of brain-derived neurotrophic factor (BDNF) (Sen et al, 2008). Reduction of regional volume in these affected brain areas has been confirmed in post-mortem studies (Stockmeier et al, 2004;Rajkowska et al, 1999) and shown to be greater in those with multiple episodes, longer illness duration (MacQueen et al, 2003), and increased symptom severity (Kumar et al, 1998).…”

The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

“…Recent functional brain imaging studies have identified critical neural circuits involving the prefrontal cortical regions, anterior cingulate, hippocampus, thalamus, basal ganglia, and amygdala that modulate emotional behavior and that are disturbed in primary and secondary mood disorders (Carlson et al, 2006). Accumulating evidence suggests an association between the hippocampal region and bipolar disorder (Brambilla et al, 2002;Velakoulis et al, 2006;Atmaca et al, 2007).…”

Advances in the treatment of anxiety: Targeting glutamate

“…Thus, enhanced glutamate release could contribute to glucocorticoid-induced neurotoxicity, 49,50 the reversal of which could be important in psychopharmacological treatment. See reviews by Manji et al 17 and Duman and Carlson et al 115,116 This shrinkage appears to disrupt the functionality of the neurons and their signaling, but it may in fact be compensatory or adaptive. 117 In postsynaptic neurons in the CNS, NMDA and AMPA receptors are actively shuttled between the membrane and cytoplasm by a clathrindependent mechanism 118 ; of note, in mature cultures, NR2B undergoes more robust endocytosis than NR2A, consistent with previous studies showing NR2A to be more highly expressed at stable synaptic sites.…”