Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex

Abstract

Background Knock-in mice with the common human BDNF Val66Met polymorphism have impaired trafficking of BDNF mRNA to dendrites. Given evidence that local synapse formation is dependent on dendritic translation of BDNF mRNA, it was hypothesized that loss-of-function Met allele mice would show synaptic deficits both at baseline and in response to ketamine, an NMDA antagonist that stimulates synaptogenesis in prefrontal cortex (PFC). Methods Whole-cell recordings from layer V medial PFC pyramidal cells in brain slices were combined with 2-photon laser scanning for analysis of WT, Val/Met, and Met/Met mice both at baseline and in response to a low dose of ketamine. Results Val/Met and Met/Met mice were found to have constitutive atrophy of distal apical dendrites and decrements in apically-targeted excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells of PFC. In addition, spine density and diameter were decreased, indicative of impaired synaptic formation/maturation (synaptogenesis). In Met/Met mice the synaptogenic effect of ketamine was markedly impaired, consistent with the idea that synaptogenesis is dependent on dendritic translation/release of BDNF. In parallel behavioral studies we found that the antidepressant response to ketamine in the forced swim test was blocked in Met/Met mice. Conclusions The results demonstrate that expression of the BDNF Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in PFC, suggesting that the therapeutic response to this drug may be attenuated or blocked in depressed patients who carry the loss of function Met allele.

State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression

“…Ketamine increases glutamate transmission in the prefrontal cortex, presumably by eliciting a disinhibition of GABAergic input that results in an enhancement of the firing rate of glutamatergic neurons thought to underlie ketamine induction of synaptogenesis (Li et al, 2010(Li et al, , 2011. Interestingly, the antidepressant effect of ketamine is attenuated in both animals and humans with the Met allele of the BDNF gene (Laje et al, 2012;Liu et al, 2012), an observation that may render BDNF genotyping an important biomarker for the clinical response to ketamine in humans. However, in our study, we did not observe a significant effect of the BDNF polymorphism.…”

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…Both processing speed and attention have been linked to dopamine functioning within prefrontal-subcortical circuits (Cropley et al, 2006), and ketamine is known to modulate dopamine signaling within the striatum and prefrontal cortex in animals (Moghaddam et al, 1997) and humans (Kegeles et al, 2000;Rabiner, 2007;Smith et al, 1998). Mechanistic studies in animals show that ketamine rapidly enhances synaptic plasticity at the level of prefrontal cortical neurons (Li et al, 2010(Li et al, , 2011, and is able to rapidly reverse stress-induced dendritic atrophy and behavioral depression in a brain-derived neurotrophic factor (BDNF)-dependent manner (Li et al, 2011;Liu et al, 2012). A recent study found that ketamine reversed deficit dopamine signaling in a learned helplessness model of depression and normalized synaptic plasticity within the nucleus accumbens (indexed by long-term potentiation) via activation of dopamine D1 receptors (Belujon and Grace, 2014).…”

Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants

“…Interestingly, this polymorphism interacts with antidepressant efficacy because Met carriers appear to exhibit a better response to classical antidepressants (Choi et al, 2006;Niitsu et al, 2013). Nevertheless, such observations are highly dependent on the type of antidepressant, gender, ethnicity and the presence of other polymorphisms (Brunoni et al, 2013;Liu et al, 2012;Tsai et al, 2010;Wang et al, 2014), suggesting only a weak association between rs6265 and antidepressant response.…”

“…Interestingly, this polymorphism interacts with antidepressant efficacy because Met carriers appear to exhibit a better response to classical antidepressants (Choi et al, 2006;Niitsu et al, 2013). Nevertheless, such observations are highly dependent on the type of antidepressant, gender, ethnicity and the presence of other polymorphisms (Brunoni et al, 2013;Liu et al, 2012;Tsai et al, 2010;Wang et al, 2014), suggesting only a weak association between rs6265 and antidepressant response.BDNF is a critical pro-survival factor for the developing and adult central nervous system, through modulation of activity-induced neuronal plasticity (Park and Poo, 2013), and has been repeatedly implicated in the etiology of depression. Moreover, its antidepressant properties are now clearly demonstrated and led to Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants…”