Hypothalamic neurons out of control

There is now considerable evidence that a number of pathophysiological conditions, including heart failure (HF), lead to excessive secretion into the blood of the neurohypophysial hormone arginine vasopressin (AVP). As HF results in reduced perfusion of the brain and other important organs, elevated AVP secretion was thought to be a normal physiological response to elevate blood pressure. However, it is now known that the persistent high levels of AVP may contribute to deleterious long term effects of HF. Thus, it important to learn how AVP secretion is elevated in HF. AVP is secreted from magnocellular neurons (MCNs) of the hypothalamic supraoptic and paraventricular nuclei that project to the pituitary. Secretion of hormones from these neurons is directly related to action potential frequency in the cell bodies and is in fact facilitated when they fire in a burst mode. One of the ways in which action potential frequency in these cells is regulated is through activation of calcium-activated potassium channels. During a burst of action potentials, calcium enters the cell and this subsequently activates a calcium-activated potassium conductance (CagK) that results in a hyperpolarization of the cell membrane. This progressively slows further action potential generation (a phenomenon known as spike frequency adaption) and may even arrest all firing as the membrane hyperpolarizes. A paper in this issue of The Journal of Physiology by Ferreira-Neto et al. (2017) examines the AHP during HF in rats. HF was induced by coronary artery ligation and 6–7 weeks later the brains were collected for patch clamp analysis of MCN electrical properties. While resting membrane potential and input resistance were unaltered, there was a reduction in the magnitude of the AHP, thus making these cells more excitable and presumably enhancing hormone secretion. The authors further use calcium imaging to show that blunted activity-evoked elevations in intracellular calcium are unlikely to be a mechanism for the reduced AHP, but report reduced transcriptional expression of the small conductance calcium-activated potassium channels SK2/SK3 that pass a substantial portion the CagK. Voltage clamp experiments measuring CagK, along with the transcriptional analysis, allow the authors to conclude that down-regulation of SK2/SK3 channels underlying the CagK is one cause of the reduced AHP in HF. Several interesting questions arise from this study. Intrinsic neuronal conductances are modulated by extrinsic synaptic inputs, as well as by concentrations of ions and various neuroactive compounds in the extracellular space. Previous work from this lab had reported alterations in synaptic inputs to MCNs in HF, in particular decreased GABAergic and increased glutamatergic signalling (Potapenko et al. 2011). This is interesting, as a well-accepted feature of many neurons is homeostatic plasticity – that is, chronically increased neuronal activity is normally associated with a compensatory down-regulation of excitatory activity and/or an increase in GABAergic activity. Somehow this appears to be absent in HF, with increased action potential frequency associated with an increased, rather than decreased synaptic excitation/inhibition ratio. It would be interesting first of all to know if homeostatic plasticity occurs in MCNs. This is important because an important player in support of homeostatic plasticity is the pro-inflammatory cytokine tumour necrosis factor alpha (TNFα). Previous work (Kang et al. 2009) has reported elevated levels of pro-inflammatory cytokines in both the circulation and in the hypothalamus in HF, and their blockade within the brain attenuates HF-associated sympathoexcitation. Could the presence over 6–7 weeks of elevated local cytokines such as either Interleukin 1β or TNFα (or their downstream mediators, such as prostaglandins), cause the transcriptional down-regulation of the SK channels reported here? There has been considerable focus upon a role for AVP in HF, but there appears to have been much less attention directed to oxytocin (OXT) actions, despite its many cardiac and anti-inflammatory actions (Gutkowska et al. 2014). In the Ferreira-Neto et al. (2017) study, recordings were presumably obtained from both AVP and OXT neurons and the AHP was reduced in all cells studied. One might question if there is elevated OXT secretion in HF and if it has physiological or pathophysiological consequences. This paper builds upon several previous studies from the Stern laboratory reporting other synaptic and conductance changes in MCNs during HF. It will be interesting to see if these occur concurrently and if the mechanistic underpinnings are identical for all. Studies such as this one highlight how in vitro slice patch clamp approaches can be used to explore the mechanisms underlying neurophysiological changes associated with peripheral cardiovascular disease. No competing interests declared.