It makes sense to consider psychopathology through the lens of the glutamatergic system because glutamate is the most prevalent excitatory neurotransmitter in the brain. Furthermore, synaptic glutamate neurotransmission is cardinal in emotion, cognition, and behavior—all phenomena inextricably linked to psychopathology. Clinical findings support dysregulated glutamate neurotransmission in cortical and limbic areas as well as variance in glutamate content in individuals with stress-related psychopathology relative to those who are psychiatrically healthy.14 It is hypothesized that the pattern and location of these synaptic alterations interact with individual and environmental characteristics to affect the clinical presentation and constellation of symptoms. Focus on glutamate-related neural remodeling and synaptic plasticity has led to a synaptic hypothesis of CSP.
Chronic stress has been associated with both synaptic potentiation and neuronal hypertrophy in brain regions including the amygdala and nucleus accumbens, as well as synaptic depression and neuronal atrophy in the prefrontal cortex, and hippocampus. The synaptic alterations in the hippocampus and prefrontal cortex are thought to be secondary to stress-induced changes in glutamate release and reuptake and astroglial loss, resulting in sustained elevations in extracellular glutamate. This precipitates reduced spine density, dendritic retraction, and branching in the prefrontal cortex as well as altered synaptic strength and excitotoxicity. The dysregulation in glutamate release and glucocorticoid signaling, together with reduced glutamate uptake and astroglial deficits, are suspected to paradoxically maintain elevated levels of extracellular glutamate despite chronic stress- induced reductions in synaptic glutamate neurotransmission.
Stress-induced synaptic hyperconnectivity in the nucleus accumbens is associated with dysregulation in monoaminergic neurotransmitters, whereas hypoconnectivity in the prefrontal cortex is associated with glutamate excitotoxicity and dysregulation. MRI studies have demonstrated that the reversal of synaptic deficits produces antidepressant-like effects and both RAADs and SAADs can reduce synaptic connectivity in the nucleus accumbens while alternately increasing connectivity in the prefrontal cortex. MRI findings have also shown reduced volume in the hippocampus and prefrontal cortex of individuals with SAAD/monoaminergic treatment-resistant depression, particularly those with impaired glutamate and γ-aminobutyric acid levels.14,15
The synaptic model of CSP has some important components:
1. The duration of stress response—as opposed to the duration of stress exposure—is critical, and the distinction between acute and chronic stress is paramount. Although there is significant individual variability in stress response and resilience, exposure to a single extreme stressor or trauma may lead to a sustained or “chronic” threat response, whereas ongoing or repeated escapable, manageable, or predictable stress exposure may lead to acute transient responses.
It is thought that acute stress exposure triggers a glutamate surge in the prefrontal cortex that results in a brief elevation in extracellular glutamate and sustained elevations in synaptic strength and NMDA and AMPA receptors. Chronic stress exposure, on the other hand, promotes reductions in prefrontal glutamate levels, synaptic strength, and NMDA and AMPA receptors with sustained elevations in extracellular glutamate.
2. Two independent pathways—hyperconnectivity in the nucleus accumbens and hypoconnectivity in the prefrontal cortex and hippocampus—may contribute to stress-related psychopathology. Patients with monoamine-based pathology show localized nucleus accumbens elevations in synaptic gain and BDNF, lack of amino acid impairment, enhanced response to monoaminergic SAADs, and increased volume in the nucleus accumbens. Patients with amino acid–based pathology demonstrate prefrontal cortex synaptic loss and excitotoxicity, amino acid impairment, and resistance to monoaminergic SAADs and have gray matter deficits in the hippocampus and prefrontal cortex (Figure 2).
Dr Averill is Clinical Research Psychologist, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT; Associate Research Scientist, Department of Psychiatry, Yale School of Medicine, New Haven, CT; and Clinical Director, Emerge Research Program, Department of Psychiatry, Yale School of Medicine. Mr Averill is Neuroimaging & Technology Manager, Emerge Research Program, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT and Department of Psychiatry, Yale University School of Medicine. Dr Abdallah is Assistant Professor of Psychiatry, Yale University School of Medicine, and Director of Neuroimaging, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD.
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