Instead, the existing repertoire of channels expressed by a neuron can be ‘rebalanced’ to correct for the deletion of an ion channel ( Swensen and Bean, 2005 Muraro et al., 2008 Andrásfalvy et al., 2008 Nerbonne et al., 2008 Van Wart and Matthews, 2006 Bergquist et al., 2010 Parrish et al., 2014 Driscoll et al., 2013). The corrective response is not limited to the de novo expression of an ion channel gene with properties that are identical to the deleted channel, as might be expected for more generalized forms genetic compensation ( El-Brolosy and Stainier, 2017 see also discussion). To date, little is understood about the underlying molecular mechanisms (but see Parrish et al., 2014 Joseph and Turrigiano, 2017 Goold and Nicoll, 2010 Mee et al., 2004).įRH induced by an ion channel gene deletion is truly remarkable. The mechanisms of FRH correct for the loss of the ion channel and precisely restore neuronal firing properties to normal, wild-type levels ( Swensen and Bean, 2005 Muraro et al., 2008 Andrásfalvy et al., 2008 Nerbonne et al., 2008 Van Wart and Matthews, 2006 Bergquist et al., 2010 Parrish et al., 2014) see also: MacLean et al., 2003 Ping and Tsunoda, 2012 Driscoll et al., 2013). In many of these examples, the genetic deletion of an ion channel is used to induce a homeostatic response. FRH has been widely documented within invertebrate neurons ( Turrigiano et al., 1994 Muraro et al., 2008 Driscoll et al., 2013) and neural circuits ( Haedo and Golowasch, 2006) as well as the vertebrate spinal cord ( Gonzalez-Islas et al., 2010), cortical pyramidal neurons ( Andrásfalvy et al., 2008) and cardiomyocytes ( Guo et al., 2005 Marrus and Nerbonne, 2008 Michael et al., 2009). We propose that FRH includes mechanisms of proteostatic feedback that act in parallel with activity-driven feedback, with implications for the pathophysiology of human channelopathies.įiring Rate Homeostasis (FRH) is a form of homeostatic control that stabilizes spike rate and information coding when neurons are confronted by pharmacological, genetic or environmental perturbation ( Davis, 2013 O'Leary et al., 2014). These different homeostatic processes have distinct effects on homeostatic synaptic plasticity and animal behavior. By contrast, expression of these genes remains unchanged in animals harboring a CRISPR-engineered, Shal pore-blocking mutation where compensation is achieved by enhanced IK DR. Eliminating Shal protein invokes Krüppel-dependent rebalancing of ion channel gene expression including enhanced slo, Shab, and Shaker.
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However, the underlying homeostatic signaling mechanisms are distinct.
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In agreement, we demonstrate robust FRH following either elimination of Kv4/Shal protein or elimination of the Kv4/Shal conductance. A prediction is that ion channel gene mutations with equivalent effects on neuronal excitability should invoke the same homeostatic response. A pervasive and intuitive theory argues that a single variable, calcium, is detected and stabilized through regulatory feedback.
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Firing rate homeostasis (FRH) stabilizes neural activity.