Synaptic Dysfunction in Depression: Potential Therapeutic Targets

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Science  05 Oct 2012:
Vol. 338, Issue 6103, pp. 68-72
DOI: 10.1126/science.1222939

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  1. Fig. 1

    Atrophy of cortical neurons is caused by chronic stress or a BDNF polymorphism. Representative confocal photomicrographs of labeled layer V pyramidal neurons in the medial PFC are shown. (Top) Effects of restraint stress (~30 min per day, 7 days) on dendrite length and branching. (Bottom left) Pyramidal neuron dendrites from wild-type (WT; Val66Val66) mice compared with mice with a knock-in of one or both Met alleles. (Bottom right) The Met allele decreases the transport of BDNF transcripts to dendrites and activity-dependent release of BDNF, which leads to atrophy of pyramidal neurons, including decreased number and length of dendrite branches. There is a gene dose effect, with Val66Met66 knock-in mice showing an intermediate effect and Met66Met66 mice a greater effect compared with WT Val66Val66 mice. Adapted from (20, 32).

  2. Fig. 2

    Chronic stress decreases synaptic connections and produces depressive-like behavior: rapid reversal by ketamine. (A) Confocal photomicrographs of labeled layer V pyramidal neurons in the medial PFC, showing the effects of CUS (21 days) on spine-synapses in layer V pyramidal neurons and reversal by a single dose of ketamine 1 day later. (B) Effects of chronic stress ± ketamine administration on 5-HT– or hypocretin (Hcrt)–induced excitatory postsynaptic potentials (EPSPs). (C and D) Quantitative analysis of the effects of CUS ± ketamine on spine density and the corresponding regulation of spine synapse function, 5-HT– or Hcrt-induced EPSP frequency (percentage of control). (E and F) Influence of CUS ± ketamine on behavior in (E) the sucrose preference test (measured by percentage of preference for a sucrose solution) and (F) novelty suppressed feeding, measured by latency to feed in an open field (measured in seconds). These models provide measures of anhedonia and anxiety, respectively, and are rapidly (1 day) reversed by ketamine, compared with the requirement for long-term administration (3 weeks) of a typical antidepressant. Error bars indicate SEM; asterisks indicate significance from control (C to F) or between CUS and CUS+ket (E, Hcrt). Adapted from (7, 20).

  3. Fig. 3

    Model depicting the synaptogenic basis of depression and treatment response. (Left) Regular mood (synaptic homeostasis). Under normal conditions, levels of synapse number and function are maintained by homeostatic mechanisms that contribute to regular mood. This includes cycling of glutamate A1 (GluA1) receptors to and from the synapse. (Middle) Depression (synaptic destabilization). Chronic stress exposure decreases synaptic density, similar to the destabilization of spine synapses that occurs under conditions that cause long-term depression (LTD). Neuronal atrophy and synaptic loss are reversible, possibly more rapidly in resilient individuals with coping, exercise, or enriched environment. Stress also decreases BDNF, and BDNF deletion mutant mice exhibit similar synaptic deficits, suggesting that this neurotrophic factor may contribute to the loss of synapses and neuronal atrophy. GSK3, which is increased in depression, can be activated by PP1 and may also contribute to synaptic destabilization by promoting the internalization of GluA1. (Right) Rapid antidepressants (synaptogenesis). Ketamine rapidly increases glutamate transmission and synaptogenesis, similar to LTP. Ketamine-induction of synaptogenesis requires BDNF/TrkB-activation of Akt and mTOR signaling, resulting in increased translation of synaptic proteins, including GluA1, as well as Arc, which is required for the expansion and stabilization of spines. The actions of ketamine are also dependent on inhibition of GSK3, which could occur via stimulation of Akt or by blockade of NMDA receptors and PP1 (not shown in the figure). Depressed patients treated with ketamine relapse after 7 to 10 days, possibly due to failure of synaptic homeostasis, which could result from genetic mutations or environmental factors such as sustained stress.

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