The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA-Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA-Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5.

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder

“…Input resistance was not altered between R59X mice and WT littermates (data not shown), suggesting that cell size does not vary significantly between genotypes. Together, these electrophysiological data demonstrate a physiologically relevant increase in synaptic GluA2-lacking AMPARs in R59X mice, consistent with the immunohistochemical results and results from published cell culture studies (Tramarin et al, 2018).…”

“…Given that previous studies support a role for CDKL5 in stabilizing excitatory synapses (Ricciardi et al, 2012;Della Sala et al, 2016) and that dysregulated GluA2 has been observed in an in vitro model of CDD (Tramarin et al, 2018), we hypothesized that R59X mice may have molecular and functional alterations in AMPAR subunits associated with the aforementioned behavioral deficits and seizure susceptibility. To investigate whether R59X mice show AMPAR subunit dysregulation, we performed western blot analysis in cortical and hippocampal tissue of membrane-bound AMPAR subunits GluA1 and GluA2, the predominant AMPAR subunits in the brain (Lu et al, 2009; Reimers Figure 3.…”

“…Given that elevated GluA2-lacking AMPARs have been previously linked to neurobehavioral deficits and Cdkl5 knockdown causes dysregulated GluA2 in neurons in vitro (Tramarin et al, 2018), we investigated levels of AMPAR subunits GluA1 and GluA2 in a novel mouse model of CDD, the Cdkl5 R59X knock-in mouse (R59X). The R59X mutation is based on the human mutation that has been observed to cause severe seizures and ID (Castrén et al, 2011) and occurs in the catalytic domain of the CDKL5 gene, resulting in premature truncation of the mRNA transcript and absence of functional CDKL5 protein.…”

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

“…Studies have been conducted to develop precise therapy based on the biological, metabolic and genetic basis of CDD. These studies include the use of NMDA (N-methyl-D-aspartate) receptor modulators [50]; allopregnanolone (a neurosteroid that restores normal microtubule morphology) [51,52]; tianeptine, which is an antidepressant affecting AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [53]; or insulin-like growth factor IGF-1 activating the Akt/mTOR pathway [54]. Hopes are related to gene therapy as a causal treatment for disorders due to CDKL5 mutations.…”

Molecular and Synaptic Bases of CDKL5 Disorder

“…For example, abnormal accumulation of GluN2B and SAP102 were observed in hippocampus of CDKL5 knockout mice (Okuda et al, 2017). The expression and surface insertion of alpha-amino-3hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPAR) was decreased by CDKL5 deficiency (Tramarin et al, 2018). Thus, CDKL5 exerts important function in maintaining mature synapse and loss of CDKL5 in mature neurons may contribute to the pathology of CDKL5 disorder.…”