Postsynaptic BDNF‐TrkB signaling in synapse maturation, plasticity, and disease

Abstract

Brain-derived neurotrophic factor (BDNF) is a prototypic neurotrophin that regulates diverse developmental events from the selection of neural progenitors to the terminal dendritic differentiation and connectivity of neurons. We focus here on activity-dependent synaptic regulation by BDNF and its receptor, full length TrkB. BDNF-TrkB signaling is involved in transcription, translation, and trafficking of proteins during various phases of synaptic development and has been implicated in several forms of synaptic plasticity. These functions are carried out by a combination of the three signaling cascades triggered when BDNF binds TrkB: The mitogen-activated protein kinase (MAPK), the phospholipase Cc (PLC PLCc), and the phosphatidylinositol 3-kinase (PI3K) pathways. MAPK and PI3K play crucial roles in both translation and/or trafficking of proteins induced by synaptic activity, whereas PLCc regulates intracellular Ca 2+ that can drive transcription via cyclic AMP and a protein kinase C. Conversely, the abnormal regulation of BDNF is implicated in various developmental and neurodegenerative diseases that perturb neural development and function. We will discuss the current state of understanding BDNF signaling in the context of synaptic development and plasticity with a focus on the postsynaptic cell and close with the evidence that basic mechanisms of BDNF function still need to be understood to effectively treat genetic disruptions of these pathways that cause devastating neurodevelopmental diseases. '

Neuroplasticity in Depressed Individuals Compared with Healthy Controls

“…Although there is limited and indirect knowledge of the processes underlying associative LTP in humans, it is believed to involve glutamate signaling and postsynaptic cell depolarization through N-methyl-Daspartate (NMDA) and a-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) receptor activation (Pittenger and Duman, 2008), which are each enhanced by BDNF (Carlson et al, 2006). Glutamate acts synergistically with BDNF and tyrosine-related kinase B (TrkB) signaling to increase NMDA activity and AMPA receptor expression (Yoshii and Constantine-Paton, 2010), both of which result in greater intracellular calcium influx. The level of postsynaptic calcium influx determines the induction of synaptic LTP or its opposite, long-term depression (LTD).…”

“…In a prior study, we compared two stimulation protocols for which robust effects have been described-paired associative stimulation (PAS) and theta burst stimulation (TBS)-and found that more consistent changes in motor cortical excitability were induced by PAS (Player et al, 2012). PAS-induced increases in cortical excitability are considered to be at least partially dependent on associative long-term potentiation (LTP) (Stefan et al, 2002), which is modulated by BDNF through both pre-and postsynaptic mechanisms (Yoshii and Constantine-Paton, 2010), known to be crucial for neuroplasticity. These mechanisms are believed to underlie motor learning and memory formation (Letzkus et al, 2007), hence providing an appropriate model for testing neuroplasticity.…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Black arrows indicate how upstream membrane receptors activate and/or regulate some of the downstream targets, illustrating crosstalk between pathways and putative shared dysregulated downstream mechanisms: MMP-9 was suggested to be regulated by mGlu 1/5 signaling (Bilousova et al, 2009) and by GABAergic signaling via an ERK-dependent mechanism (Miao et al, 2010). ERK1/2 and PI3K are regulated by mGlu 1/5 (Banko et al, 2006) and by TrkB signaling (Yoshii and Constantine-Paton, 2010). ERK1/2 was shown to signal downstream of D 1/5 (Beaulieu and Gainetdinov, 2011).…”

Serum inducible kinase is a positive regulator of cortical dendrite development and is required for BDNF-promoted dendritic arborization

“…Together, our results reveal that SNK is critical for dendritic morphogenesis throughout neuronal development, which is important for circuit structure and function. BDNF is also essential for many aspects of circuit establishment [46] and functions [47], such as learning and memory (long-term potentiation and long-term depression) [47], synaptic homeostasis [48], and epileptogenesis [49]. In addition, aberrant BDNF signaling is involved in an array of neurological disorders, including mental retardation, autism, epilepsy, and neurodegenerative diseases [47].…”

“…BDNF is also essential for many aspects of circuit establishment [46] and functions [47], such as learning and memory (long-term potentiation and long-term depression) [47], synaptic homeostasis [48], and epileptogenesis [49]. In addition, aberrant BDNF signaling is involved in an array of neurological disorders, including mental retardation, autism, epilepsy, and neurodegenerative diseases [47]. Interestingly, SNK is regulated by LTP and epileptic stimuli [14], and is implicated in Parkinson disease and Alzheimer disease via α-synuclein phosphorylation [50][51][52].…”