A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor

Abstract

Cardiac function is modulated by norepinephrine release from innervating sympathetic neurons. These neurons also form excitatory connections onto cardiac myocytes in culture. Here we report that brain-derived neurotrophic factor (BDNF) altered the neurotransmitter release properties of these sympathetic neuron-myocyte connections in rodent cell culture, leading to a rapid shift from excitatory to inhibitory cholinergic transmission in response to neuronal stimulation. Fifteen minutes of BDNF perfusion was sufficient to cause this shift to inhibitory transmission, indicating that BDNF promotes preferential release of acetylcholine in response to neuronal stimulation. We found that p75(-/-) neurons did not release acetylcholine in response to BDNF and that neurons overexpressing p75 showed increased cholinergic transmission, indicating that the actions of BDNF are mediated through the p75 neurotrophin receptor. Our findings indicate that p75 is involved in modulating the release of distinct neurotransmitter pools, resulting in a functional switch between excitatory and inhibitory neurotransmission in individual neurons.

Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties

“…Under these conditions, the sympathetic neurons extend processes and form active synapses onto neighboring neurons and myocytes, as well as forming autaptic synapses onto themselves (Bunge et al, 1974; O'Lague et al, 1974; Lockhart et al, 1997; Yang et al, 2002). Interestingly, co-culture of initially noradrenergic superior cervical sympathetic neurons with other tissues, such as cardiac myocytes, leads to a time-dependent increase in cholinergic and mixed noradrenergic/cholinergic neurotransmission at synapses between sympathetic neurons and myocytes (Furshpan et al, 1976; O'Lague et al, 1978c; O'Lague et al, 1978b, a; Furshpan et al, 1986b; Potter et al, 1986).…”

“…As will be detailed below, neurotrophins rapidly influence neurotransmission in cultured sympathetic neurons in a manner that is differentially regulated through different neurotrophin receptors (Lockhart et al, 1997; Yang et al, 2002; Slonimsky et al, 2003; Slonimsky et al, 2006). Therefore it will be helpful to briefly review neurotrophin receptor expression in sympathetic neurons, for a more detailed treatment see (Chao and Hempstead, 1995; Chao, 2003; Reichardt, 2006).…”

“…Trk and p75 receptors have complex, interacting signaling responses and, in some instances have opposing effects on a range of neuronal properties, including cell survival, process outgrowth, neurotransmission and firing properties (Barrett and Bartlett, 1994; Chao and Hempstead, 1995; Dechant and Barde, 2002; Yang et al, 2002; Lu et al, 2005; Woo et al, 2005; Luther and Birren, 2009). In cells that co-express both p75 and Trk receptors there is evidence for complex interactions between their respective signaling pathways.…”

“…Sympathetic neurons grown in this manner form functional synaptic contacts with myocytes that are similar to the anatomy seen in vivo (Smolen, 1988). Myocytes in these cultures beat spontaneously, and the beat rate is influenced by synaptic transmission from connected sympathetic neurons (Conforti et al, 1991; Lockhart et al, 1997; Yang et al, 2002). Using electrophysiological techniques the neurons can be stimulated to fire action potentials at controlled frequencies to induce transmitter release, the effect of which can be observed as a change in the beat rate of the myocyte (Conforti et al, 1991; Lockhart et al, 1997; Yang et al, 2002).…”

“…Myocytes in these cultures beat spontaneously, and the beat rate is influenced by synaptic transmission from connected sympathetic neurons (Conforti et al, 1991; Lockhart et al, 1997; Yang et al, 2002). Using electrophysiological techniques the neurons can be stimulated to fire action potentials at controlled frequencies to induce transmitter release, the effect of which can be observed as a change in the beat rate of the myocyte (Conforti et al, 1991; Lockhart et al, 1997; Yang et al, 2002). Within the first few days in co-culture superior cervical sympathetic neurons express almost exclusively NE, which is an excitatory transmitter for myocytes.…”