Plasticity and metaplasticity are hallmark features of the neural system controlling breathing. Respiratory plasticity is a persistent change in breathing control following transient stimuli. Metaplasticity is a change in the capacity to express plasticiy (plastic plasticity). One well-studied model of respiratory plasticity is phrenic long- term facilitation (pLTF), a persistent increase in phrenic motor output following exposure to moderate acute intermittent hypoxia (AIH). Preconditioning with repetitive acute intermittent hypoxia (rAIH) or chronic intermittent hypoxia (CIH) enhances pLTF, demonstrating a degree of respiratory metaplasticity. Multiple cellular mechanisms give rise to phenotypically similar long-lasting phrenic motor facilitation (pMF), including the so-called Q and S pathways to pMF. These pathways are named for the G proteins initiating plasticity. For example, moderate AIH-induced pLTF requires Gq-coupled 5-HT2 receptor activation, protein kinase C (PKC) activity, new synthesis of brain derived neurotrophic factor (BDNF) and downstream signaling via TrkB and ERK MAP kinases. Conversely, stimulation of Gs coupled 5-HT7 receptors activates cAMP, inducing new synthesis of an immature TrkB isoform and downstream protein kinase B/Akt activation. Normally, the Q and S pathways interact via mutual (cross-talk) inhibition. Thus, in normal rats, the dominant Q pathway to pLTF is constrained by sub-threshold S pathway activation (eg. by 5-HT7 receptor activation). The fundamental hypothesis guiding this proposal is that rAIH preconditioning elicits pLTF metaplasticity by reducing cross-talk inhibition between the S and Q pathways to pMF, thereby enhancing pLTF following moderate AIH by enabling independent contributions from both pathways. Thus, we predict that rAIH-enhanced pLTF (ie. metaplasticity) results from independent contributions from both 5-HT2 and 5-HT7 receptor activation. This research is significant from a biological perspective since it advances our understanding of basic mechanisms giving rise to respiratory motor plasticity and meta-plasticity. It is significant from a clinical perspective since rAIH has considerable therapeutic potential in debilitating clinical disorders that compromise respiratory and non-respiratory motor function.
This research is significant from a biological perspective since it advances our understanding of basic mechanisms giving rise to respiratory motor plasticity and meta-plasticity. It is significant from a clinical perspective since repetitive acute intermittnt hypoxia (rAIH) has considerable therapeutic potential in debilitating clinical disorders that compromise respiratory and non-respiratory motor function in humans (Trumbower et al. 2012; Hayes et al. 2014). To develop this safe, simple and (potentially) effective therapeutic tool in motor rehabilitation, a fundamental understanding of mechanisms giving rise to rAIH-induced metaplasticity is essential. This is an important clinical goal since respiratory insufficiency is he major cause of morbidity and mortality in traumatic spinal injury as well as most neurodegenerative and/or genetic neurological diseases.
| Fields, D P; Mitchell, G S (2017) Divergent cAMP signaling differentially regulates serotonin-induced spinal motor plasticity. Neuropharmacology 113:82-88 |
