Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

Abstract

Purpose of review: Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.

Recent findings: Here, we will briefly review evidence that PTSD might be a "synaptic disconnection syndrome" and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.

Keywords: Connectivity; Glutamate; Ketamine; NMDA; PTSD; Plasticity; Synapse.

Fig. 1

Stress causes neural atrophy and synapse loss. a The influence of repeated-restraint stress (7 d) on pyramidal neurons (layer V) in the medial prefrontal cortex (mPFC) of rat. The left-hand set of images shows that stress reduces the number and length of apical dendrites. The right-hand set of images shows a magnified segment of dendrite, with its spines at the point of synaptic contacts with neuronal inputs to the mPFC; repeated stress significantly decreases the number of spine synapses. b Under normal conditions, stimulation of the presynaptic neuron releases glutamate, resulting in the activation of postsynaptic glutamate AMPA receptors and depolarization; this causes activation of multiple intracellular pathways, including the BDNF-TrkB signaling pathway (and the downstream kinases Akt and ERK) and the mTORC1 pathway. These pathways are essential for regulation of synaptic plasticity, a fundamental adaptive learning mechanism that includes maturation (increased spine-head diameter) and an increase in the number of synapses. This process requires mTORC1-mediated de novo protein synthesis of synaptic proteins, including glutamate GluA1AMPA receptors and PSD95. Repeated stress decreases BDNF and mTORC1 signaling in part via upregulation of the negative regulator REDD1 (regulated in DNA damage and repair), which decreases the synthesis of synaptic proteins and thereby contributes to a decreased number of spine synapses. Other proteins that are involved in the regulation of synaptic plasticity include GSK3 and protein phosphatase 1 (PP1) (from [23•])

Fig. 2

Evidence that voluntary exercise increases dendritic spine density in the dentate gyrus of the hippocampus in rats. The left figure presents the number of dendritic spines per 10 μm for dentate granule cells. The asterisk symbol indicates p < .05. The right figure presents results from Golgi-impregnated dentate granule cells at ×100 magnification from control (A) and exercised (B) animals. Scale bar = 10 μM [82]

Fig. 3

This figure illustrates a “vicious cycle” through which neuroinflammation, HPA activation, and stress-related alterations in circuit function interact to contribute to synaptic loss and how synaptic loss then contributes to the chronicity of PTSD by compromising the regulation and neuroplasticity of emotion-related neural networks (modified from [101])

Fig. 4

Confocal photomicrographs of labeled layer V pyramidal neurons in the medial prefrontal cortex. The left figure shows the low numbers of dendritic spines present in the dendrites of layer V pyramidal neurons after 21 days of chronic uncontrollable stress (CUS). The right figure illustrates the reversal by a single dose of ketamine 1 day later. Red arrows highlight dendritic spines present after ketamine

Fig. 5

Ketamine causes a burst of glutamate that is thought to occur via disinhibition of GABA interneurons; the tonic firing of these GABA interneurons is driven by NMDA receptors, and the active, open-channel state allows ketamine to enter and block channel activity. The resulting glutamate burst stimulates AMPA receptors, which causes depolarization and activation of voltage-dependent Ca²⁺ channels (VDCC), leading to release of BDNF and stimulation of TrkB receptors and activation of Akt, which then increases mTORC1 signaling, leading to the increased synthesis of proteins that are required for synapse maturation and formation (i.e., GluA1 and PSD95). Under conditions in which BDNF release is blocked or neutralized, or in which mTORC1 signaling is blocked by rapamycin, the synaptic and behavioral actions of ketamine are blocked. Scopolamine also causes a glutamate burst via blockade of acetylcholine muscarinic M₁ (ACh-M₁) receptors on GABA interneurons. Antagonists ofmGluR2/3 also produce rapid antidepressant actions via blockade of presynaptic autoreceptors that inhibit the release of glutamate. Relapse to a depressive state is associated with a decrease of synapses on mPFC neurons, which could occur via stress and imbalance of endocrine hormones (cortisol), estrogen, inflammatory cytokines, and metabolic and cardiovascular illnesses (from [23•])