Food deprivation induces presynaptic plasticity in the autonomic nervous system

The sympathetic-adrenal medullary nervous system is a key component of the response of mammals to maintain homeostasis during stress. This notion was first articulated by Walter B. Cannon in the early 20th century, who introduced the term “fight or flight” response. Hans Selye promoted the notion of a unified, systemic and nonspecific response to a variety of stressors that includes all parts of the sympathetic nervous system (1). However, more recently it has become evident that different stressors can elicit different sympathetic responses. One example is hypoglycemia. Hypoglycemia causes the splanchnic nerve, whose cell bodies are in the spinal cord, to stimulate chromaffin cells in the adrenal medulla to release epinephrine into the circulation. The increased epinephrine has numerous metabolic effects that increase blood glucose. Hypoglycemia causes little or no activation of postganglionic, noradrenergic sympathetic nerves, another major component of the sympathetic nervous system (2, 3). In PNAS Wang et al. investigate the response of the sympathetic nervous system to fasting, a stress similar to hypoglycemia (4). The authors find that the sympathetic response is also isolated to the adrenal medullary pathway. Unexpectedly, their study suggests that an important component of the increased secretion of epinephrine results from increased efficiency of cholinergic transmission between the splanchnic nerve terminal and the chromaffin cell. Further investigation suggests that this synaptic plasticity results from a paracrine system within the adrenal medulla.

Wang et al. (4) first demonstrate that mice that are food-deprived for 24 h had normal plasma glucose, elevated urinary epinephrine, and normal urinary norepinephrine. Because the source of epinephrine is the adrenal medulla and the source of norepinephrine is mainly sympathetic nerves, these results confirm the expected physiology that the metabolic stress of starvation specifically activates the adrenal medullary component of the sympathetic nervous system. The effects of food deprivation are countered by the peripheral effects of elevated circulating epinephrine to maintain plasma glucose homeostasis. Although not investigated, the central nervous system may have increased the frequency of nerve impulses in the splanchnic nerve, innervating the adrenal medulla. However, Wang et al. (4) focus on another aspect of regulation that had not been previously considered. They investigated the strength of the synapses between cholinergic splanchnic nerve terminals and chromaffin cells upon food deprivation (Fig. 1). First, they electrically stimulated the presynaptic nerve terminals. The authors found that the excitatory postsynaptic currents (EPSCs) were significantly larger following food deprivation. The larger EPSCs could reflect an increase in presynaptic exocytosis, increased sensitivity of chromaffin cells to acetylcholine, or both. The second approach indicated that a component of the increased synaptic transmission is presynaptic.

Fig. 1.

Plasticity in an autonomic synapse in the adrenal medulla helps maintain euglycemia and requires autocrine/paracrine modulation. Evidence is presented that mice maintain euglycemia during food deprivation because of increased secretion of epinephrine from the adrenal medulla. A component of the starvation-dependent increase of epinephrine secretion was an unexpected increase in the efficiency of splanchnic nerve synaptic transmission induced by an autocrine/paracrine feedback pathway at the splanchnic nerve/ chromaffin cell synapse. Wang et al. (4) provide evidence that the increase in release probability of cholinergic vesicles results from increased expression of NYP in chromaffin cells that, upon release, interacts with Y5-type NPY receptors on the splanchnic nerve terminal.

Wang et al. (4) used the paired-pulse ratio technique to probe presynaptic mechanisms. Presynaptic nerves are stimulated with two identical depolarizations tens of milliseconds apart. If the response to the second stimulus is reduced compared with that of the first response, then the first response has partially saturated the ability of the synapse to respond to the second stimulus. The authors found that fasting reduced the ratio of the second EPSC to the first EPSC, indicating stronger presynaptic exocytosis. There was no detectable alteration in the secretory response of chromaffin cells (measured by amperometry) to electrophysiological depolarization, thereby indicating that the secretory pathway in chromaffin cells was not significantly altered.

Wang et al. (4) also found that fasting caused increases in the expression of the transcription factor CREB, and of neuropeptide-Y (NPY), which is stored in secretory granules. NPY is normally expressed in chromaffin cells in the adrenal medulla and in CNS neurons, including those in the hypothalamus. It plays an important role in appetite and energy metabolism. Its expression in the adrenal medulla also increased upon insulin-induced hypoglycemia (5). To investigate a role for NPY in the splanchnic nerve-chromaffin cell plasticity, the above experiments were repeated in NPY knockout mice. Plasma glucose levels were reduced and urinary epinephrine was not elevated in the knockout mice subjected to starvation. In addition, EPSC amplitude was decreased and the paired-pulse ratio was increased (suggesting reduced presynaptic strength). Thus, the homeostatic response to food deprivation was reduced in the absence of NPY. However, the global knockout of NPY is a blunt tool that could result in developmental changes and systemic effects because of behavioral and metabolic changes independent of the adrenal medulla.

Wang et al. (4) take a more nuanced approach by manipulating NPY signaling in vitro in adrenal slices from fed, wild-type mice. Incubation with NPY for several hours reduced the paired-pulse ratio (indicating an increase in presynaptic strength). The effect was mimicked by a Y5 NPY receptor agonist and blocked by a Y5 antagonist. Conversely, Y1 or Y2 NPY receptor antagonists (all three receptor subtypes are expressed in mouse adrenal medulla) had no effect on the paired-pulse ratio. Importantly, the Y5 antagonist added to slices reversed the effects of food deprivation. Finally, the authors demonstrate that administration of the Y5 antagonist to wild-type mice altered the homeostatic response to food deprivation in the living animals. Plasma glucose was reduced and urinary epinephrine was not increased. These results suggest that the increased expression of NPY upon food deprivation increases NPY secretion and activation of Y5 NPY receptors, presumably on the splanchnic nerve terminal, to enhance the probability of exocytosis of cholinergic synaptic vesicles.

Synaptic plasticity has been intensively investigated in the CNS. To our knowledge, the present study (4) is the first to demonstrate plasticity in an autonomic synapse. The study suggests a surprising autocrine/paracrine transsynaptic signaling pathway that involves secretion of NPY from postsynaptic chromaffin cells (Fig. 1). However, this study is only the beginning of the story and leaves many questions unanswered. What is the pathway that increases NPY expression upon food deprivation? Does the synaptic plasticity include a postsynaptic change in cholinergic signaling? Is there increased CNS drive of the splanchnic nerve during food deprivation that contributes to increased epinephrine secretion from chromaffin cells? Because the global knockout of NPY can have many affects, it will be important to determine whether local knockout of NPY in the adrenal medulla that is timed to occur in the adult mouse prevents the homeostatic response. Finally, is the Y5 receptor truly on the nerve terminal of the splanchnic nerve, and what is the signaling pathway activated by NPY Y5 receptor that increases nerve terminal release probability?