proBDNF and p75NTR Control Excitability and Persistent Firing of Cortical Pyramidal Neurons

Abstract

Persistent firing of entorhinal cortex (EC) pyramidal neurons is a key component of working and spatial memory. We report here that a pro-brain-derived neurotrophic factor (proBDNF)-dependent p75NTR signaling pathway plays a major role in excitability and persistent activity of pyramidal neurons in layer V of the EC. Using electrophysiological recordings, we show that proBDNF suppresses persistent firing in entorhinal slices from wild-type mice but not from p75NTR-null mice. Conversely, function-blocking proBDNF antibodies enhance excitability of pyramidal neurons and facilitate their persistent firing, and acute exposure to function-blocking p75NTR antibodies results in enhanced firing activity of pyramidal neurons. Genetic deletion of p75NTR specifically in neurons or during adulthood also induces enhanced excitability and persistent activity, indicating that the proBDNF-p75NTR signaling cascade functions within adult neurons to inhibit pyramidal activity. Phosphatidylinositol 4,5-bisphosphate (PIP2)-sensitive transient receptor potential canonical channels play a critical role in mediating persistent firing in the EC and we hypothesized that proBDNF-dependent p75NTR activation regulates PIP2 levels. Accordingly, proBDNF decreases cholinergic calcium responses in cortical neurons and affects carbachol-induced depletion of PIP2. Further, we show that the modulation of persistent firing by proBDNF relies on a p75NTR-Rac1-PI4K pathway. The hypothesis that proBDNF and p75NTR maintain network homeostasis in the adult CNS was tested in vivo and we report that p75NTR-null mice show improvements in working memory but also display an increased propensity for severe seizures. We propose that the proBDNF-p75NTR axis controls pyramidal neuron excitability and persistent activity to balance EC performance with the risk of runaway activity.

Neurobiology of local and intercellular BDNF signaling

“…While BDNF has the ability to increase neuronal excitability and synaptic strength [5, 20, 71, 76, 78, 130, 171], proBDNF can reduce neuronal excitability, decrease synaptic efficiency, and facilitate synaptic depression [53, 98, 126, 162, 165, 167]. …”

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

“…Increased complexity of the dendritic spines of CA1 hippocampal pyramidal neurons, changes to glutamatergic receptors, and increased cholinergic transferase activity in p75 exonIII−/− mice have also been demonstrated [124,131,133,134]. In addition, it has been reported that, in adult mice lacking p75 NTR , the excitability and persistent firing of pyramidal neurons in layer 5 of the entorhinal cortex is unregulated due to a lack of inhibition [135]. As the expression of p75 NTR in the entorhinal cortex occurs in the innervating cBF axons, the role of p75 NTR could be to regulate cBF neuron structure or function thereby indirectly mediating the inhibition or activation of post-synaptic pyramidal cell activity.…”

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

“…) and suppressed persistent firing (Gibon et al . ), respectively. These results suggest that proBDNF can also act as an endogenous ligand to directly regulate LTD and to control neuron excitability.…”

“…Likewise, the unprocessed neurotrophin 3 (proNT3) triggers apoptosis in inner ear neurons and sympathetic neurons which co-express p75NTR and sortilin (Yano et al 2009;Tauris et al 2011). Application of proBDNF to p75NTR-expressing hippocampal or entorhinal slices enhanced long-term depression (LTD) (Woo et al 2005) and suppressed persistent firing (Gibon et al 2015), respectively. These results suggest that proBDNF can also act as an endogenous ligand to directly regulate LTD and to control neuron excitability.…”