PgmNr Z624: MECP2-IGF1 signaling determines how neural circuits interpret sensory information.

Authors:
Nicholas Santistevan; Cole Gilsdorf; Marc Wolman


Institutes
University of Wisconsin - Madison, Madison, WI.


Abstract:

            Rett Syndrome (RTT) is an X-linked neurodevelopmental, autism spectrum disorder that affects 1 in 10,000 females and is characterized by motor and cognitive impairment. RTT is caused by dysfunction of the methyl-CpG-binding protein 2 (mecp2) gene; a transcriptional regulator known to promote neuron development and function. Despite mecp2’s association with RTT, it remains poorly understood how MECP2 activity influences circuits comprised of various neuron types to control distinct aspects of behavior.

            Larval stage behavioral analyses revealed that mecp2 mutants exhibit reduced prepulse inhibition (PPI) of the acoustic startle response (ASR); and therefore, indicate a critical role for mecp2 in the ASR circuits’ ability to interpret sensory information. Stimulus interpretation is often impaired in autism spectrum disorders, but is typically attributed to sensory or motor defects. Notably, the mecp2 mutants show normal acoustic sensitivity, execute a normal ASR, and habituate to repetitive acoustic stimulation; and therefore, indicate a specific, central role for mecp2 in regulating PPI. Consistent with published reports, inhibition of NMDA-type glutamate receptors or GABA-A receptors reduces PPI in wild type and strengthens the mecp2 mutants’ PPI deficit. In contrast, stimulation of glutamatergic or GABAergic signaling in mecp2 mutants reverses their PPI deficit. These results, coupled with our understanding of the ASR circuit’s cellular makeup, suggest that mecp2 is required for a feedforward inhibitory microcircuit that uses glutamate and GABA to suppress Mauthner neuron activity and hence, drive PPI. Imaging of this feedforward microcircuit revealed developmental defects in mecp2 mutants.

            As a transcriptional regulator, mecp2 likely influences circuit development and function by activating or suppressing specific genes. For example, mecp2 stimulates expression of igf1; a vital regulator of circuit formation and function. IGF1 recently became a promising therapeutic target for RTT when IGF1 stimulation was found to reverse motor defects in MECP2 deficient mice. To determine whether mecp2 acts through IGF1 signaling to control PPI, we combined genetic and pharmacological manipulations to attenuate and stimulate IGF1 signaling in wild type and mecp2 mutants, respectively. Induction of a dominant negative igfr1a reduced PPI, suggesting that IGF1R activity is required for PPI. Stimulation of IG1R signaling in mecp2 mutants was sufficient to improve PPI in mecp2 mutants. Together, these results support the model that mecp2 promotes IGF1 signaling to regulate how a neural circuit interprets sensory information.



ZFIN Genetics Index
1. mecp2