Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders

Abstract

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.

Figure 1.. Hebbian versus Homeostatic Synaptic Plasticity

This figure depicts key distinguishing properties of Hebbian versus Homeostatic synaptic plasticity. During Hebbian plasticity, synaptic strength is modified in the same direction of the applied stimuli. For instance, strong stimulation (e.g. theta burst; 5 pulses at 100 Hz applied every second) or coincidence of presynaptic and postsynaptic activity (also called “pairing”) leads to an increase in synaptic strength resulting in Long Term Potentiation (LTP). In contrast, sustained low frequency stimulation (e.g. 1 Hz for 10–15 min) weakens synaptic strength leading to Long Term Depression (LTD). In contrast, homeostatic plasticity changes in neuronal network activity or alterations in synaptic inputs lead to an adjustment of synaptic strengths in the opposite direction (i.e. in a negative feedback manner) to bring neuronal activity patterns back to their initial set point. For instance, global silencing of activity leads to an increase in synaptic strength, whereas augmentation of activity results in downregulation of synaptic efficacy.

Figure 2.. Examples of Multiplicative Synaptic Scaling

Multiplicative synaptic scaling involves up- or down-regulation of synaptic weights on a given neuron by a constant factor. During these forms of plasticity, synaptic weights are scaled up or down in a negative feedback manner to counter the chronic activity levels detected in the cell. As a rule, “homeostatic synaptic scaling” is expected to preserve relative strengths of synapses. Unlike Hebbian forms of plasticity, synaptic scaling does not alter the relative strength of a synapse with respect to its neighbors on a neuron. The figure depicts three representative postsynaptic spines on a neuron which possess 15, 10 and 5 receptors on their surface. If these synapses go through 20% synaptic downscaling or upscaling, the receptor numbers decrease (left) or increase (right) by 20% (±3, ±2, ±1) respectively.

Figure 3.. Ketamine and Lithium Elicit Multiplicative Synaptic Scaling

This figure depicts the synaptic action of ketamine and lithium on a neuron detected via whole cell voltage clamp recordings. Brief (1–3 hour) application of ketamine or other NMDA receptor blockers results in homeostatic upscaling of unitary synaptic responses (red traces). In contrast, chronic (~10–11 days) treatment of neurons with 1 mM lithium chloride results in marked synaptic downscaling (yellow traces). Despite their widely divergent targets and mechanisms of action, in preclinical models both treatments utilize the same synaptic process (i.e. synaptic scaling), albeit in opposite directions. The graph shows the tabulation of results from experiments where unitary excitatory postsynaptic current amplitudes are ranked from lowest to highest. These plots can be fitted with a line and ketamine or lithium treatment selectively increases or decreases the slope of the respective linear plot. The difference between the slopes of linear plots depicting unitary EPSC amplitudes after drug treatment and controls correspond to the “multiplicative factor” underlying the change in synaptic strength.

Figure 4.. Model for Ketamine Action and Regulation of Protein Synthesis

Left, Spontaneous glutamate release and NMDA receptor activation leads Ca²⁺ influx (even when Mg²⁺ is present see Reese and Kavalali, 2015). In turn, Ca²⁺-Calmodulin complexes activate eEF2 kinase leading to phosphorylation of eEF2 and suppression of protein translation. Right, Ketamine blocks this resting NMDA receptor activity leading to a decrease in Ca²⁺-Calmodulin complexes and deactivation of eEF2 kinase. Subsequent decrease in the amount of phosphorylated eEF2 elicits desuppression of dendritic protein translation, ultimately triggering synaptic upscaling (Sutton et al., 2006; Autry et al., 2011; Nosyreva et al., 2013, Reese and Kavalali, 2015).

Figure 5.. A synaptic model illustrating a putative mechanism by which Li+ treatment leads to enhanced AMPAR endocytosis and downscaling of synaptic responses.

Several studies suggest that lithium can impact gene transcription via GSK3-β and β-catenin signaling. There is evidence that chronic lithium exposure leads to sustained elevation in BDNF levels, which in turn impacts surface levels of AMPA receptors via activation of its high affinity receptor TrkB. Importantly, recent work has identified dynamin-dependent endocytosis acting in conjunction with BDNF-TrkB signaling as a key target of lithium’s effects on synaptic function. According to this model, chronic lithium administration — that triggers anti-manic behavior — elicits synaptic downscaling via dynamin-dependent endocytosis of AMPA receptors. Here, in addition to alterations in gene transcription, lithium may directly impact AMPA receptor endocytosis by regulation of dynamin phosphorylation due to its inhibition of GSK3-β (see Gideons et al., 2017).