Fragile X Syndrome is a genetic form of intellectual disability associated with autism, epilepsy and mood disorders. Electrophysiology studies in Fmr1 knockout (KO) mice, a murine model of Fragile X Syndrome, have demonstrated alterations of synaptic plasticity, with exaggerated long‐term depression induced by activation of metabotropic glutamate receptors (mGluR‐LTD) in Fmr1 KO hippocampus. We have previously demonstrated that activation of serotonin 5‐HT7 receptors reverses mGluR‐LTD in the hippocampus of wild‐type and Fmr1 KO mice, thus correcting a synaptic dysfunction typically observed in this disease model. Here we show that pharmacological inhibition of cyclin‐dependent kinase 5 (Cdk5, a signaling molecule recently shown to be a modulator of brain synaptic plasticity) enhanced mGluR‐LTD in wild‐type hippocampal neurons, which became comparable to exaggerated mGluR‐LTD observed in Fmr1 KO neurons. Furthermore, Cdk5 inhibition prevented 5‐HT7 receptor‐mediated reversal of mGluR‐LTD both in wild‐type and in Fmr1 KO neurons. Our results show that Cdk5 modulates hippocampal synaptic plasticity. 5‐HT7 receptors require Cdk5 to modulate synaptic plasticity in wild‐type and rescue abnormal plasticity in Fmr1 KO neurons, pointing out Cdk5 as a possible novel target in Fragile X Syndrome.

Mitochondria in neurons contribute to energy supply, the regulation of synaptic transmission, Ca²⁺ homeostasis, neuronal excitability, and stress adaptation. In recent years, several studies have highlighted that the neurotransmitter serotonin (5-HT) plays an important role in mitochondrial biogenesis in cortical neurons, and regulates mitochondrial activity and cellular function in cardiomyocytes. 5-HT exerts its diverse actions by binding to cell surface receptors that are classified into seven distinct families (5-HT1 to 5-HT7). Recently, it was shown that 5-HT3 and 5-HT4 receptors are located on the mitochondrial membrane and participate in the regulation of mitochondrial function. Furthermore, it was observed that activation of brain 5-HT7 receptors rescued mitochondrial dysfunction in female mice from two models of Rett syndrome, a rare neurodevelopmental disorder characterized by severe behavioral and physiological symptoms. Our Western blot analyses performed on cell-lysate and purified mitochondria isolated from neuronal cell line SH-SY5Y showed that 5-HT7 receptors are also expressed into mitochondria. Maximal binding capacity (Bmax) obtained by Scatchard analysis on purified mitochondrial membranes was 0.081 pmol/mg of 5-HT7 receptor protein. Lastly, we evaluated the effect of selective 5-HT7 receptor agonist LP-211 and antagonist (inverse agonist) SB-269970 on mitochondrial respiratory chain (MRC) cytochrome c oxidase activity on mitochondria from SH-SY5Y cells. Our findings provide the first evidence that 5-HT7 receptor is also expressed in mitochondria.

Phosphodiesterase 2A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cortex and hippocampus, PDE2A expression level is upregulated in Fmr1 -KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a ^+/− mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a ^+/− females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of GluR1 in CA1, producing reduced mGluR-dependent LTD. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer Disease, schizophrenia, FXS as well as other forms of ASD.