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Neurobiol Dis. 2019 Oct;130:104482. doi: 10.1016/j.nbd.2019.104482. Epub 2019 May 23.

The loss of β adrenergic receptor mediated release potentiation in a mouse model of fragile X syndrome.

Author information

1
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain; Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain.
2
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain.
3
Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain.
4
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, 28040 Madrid, Spain; Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense, 28040 Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain. Electronic address: jsprieto@vet.ucm.es.

Abstract

In fragile X syndrome, the absence of Fragile X Mental Retardation Protein (FMRP) is known to alter postsynaptic function, although alterations in presynaptic function also occur. We found that the potentiation of glutamate release induced by the β adrenergic receptor (βAR) agonist isoproterenol is absent in cerebrocortical nerve terminals (synaptosomes) from mice lacking FMRP (Fmr1 KO), despite the normal cAMP generation. The glutamate release induced by moderate stimulation of synaptosomes with 5 mM KCl was not potentiated in Fmr1 KO synaptosomes by isoproterenol, nor by stimulating the receptor associated signaling pathway with the adenylyl cyclase activator forskolin or with the Epac activator 8-pCPT. Hence, the impairment in the pathway potentiating release is distal to βARs. Electron microscopy shows that Fmr1 KO cortical synapses have more docked vesicles than WT synapses, consequently occluding the isoproterenol response through which more SVs approach the active zone (AZ) of the plasma membrane. Weak stimulation of synaptosomes with the Ca2+ ionophore ionomycin recovered the release potentiation driven by forskolin and 8-pCPT but not with isoproterenol, revealing an impairment in the efficiency of receptor generated cAMP to activate the release potentiation pathway. Indeed, inhibiting cyclic nucleotide phosphodiesterase PDE2A with BAY 60-7550 reestablished isoproterenol mediated potentiation in Fmr1 KO synaptosomes. Thus, the lack of β-AR mediated potentiation of glutamate release appears to be the consequence of an impaired capability of the receptor to mobilize SVs to the AZ and because of a decreased efficiency of cAMP to activate the signaling pathway that enhances neurotransmitter release.

KEYWORDS:

Cerebrocortical nerve terminals; Docked synaptic vesicles; Fmr1 KO mice; Fragile X syndrome; Glutamate release; Phosphodiesterase 2; Ready releasable pool; cAMP; β adrenergic receptors

PMID:
31129085
DOI:
10.1016/j.nbd.2019.104482

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