Rett syndrome (RTT) is a severe neurodevelopmental disorder with autistic features caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999). Studies in genetic mouse models indicate that Mecp2 mutation results in deficits in brain microcircuitry, including reduced dendritic spine density, excitatory/inhibitory (E/I) imbalance and altered functional connectivity (Shepherd & Katz, 2011; Katz et al., 2012) and that restoration of Mecp2 gene function can significantly reverse disease symptoms (Guy et al., 2007). Although loss of MeCP2 results in dysregulation of many genes, reduced levels of Brain Derived Neurotrophic Factor (BDNF), a key neuronal signaling molecule, are thought to play an important role in the pathophysiology of RTT (Katz, 2014; Li and Pozzo-Miller, 2014). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2 null mice (Kline et al., 2010), suggesting that therapies targeting BDNF or its receptor, TrkB, may be effective at acute reversal of respiratory abnormalities in RTT. To approach this issue we examined the ability of LM22A-4, a small molecule BDNF loop domain mimetic and TrkB partial agonist (Massa et al., 2010), to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants (Kron et al., 2014). Patch clamp recordings in Mecp2 null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in nTS. In vivo, acute treatment of Mecp2 null and heterozygous mutants with LM22A-4 completely eliminates spontaneous apneas as well as respiratory dysregulation during behavioral arousal, a prominent feature of human RTT. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked and establish the proof-of-concept that treatment with a small molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice. Supported by NS057398 (NINDS), the Rett Syndrome Research Trust and Autism Speaks.

Therapeutic strategies for restoring excitatory/inhibitory balance in Rett syndrome: Focus on BDNF/TrkB signaling

249th National Meeting (2015)

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