Dampened dopamine‐mediated neuromodulation in prefrontal cortex of fragile X mice

Key pointsActivation of D1 receptors produces an initial suppression followed by facilitation of evoked inhibitory postsynaptic currents (IPSCs) in layer II pyramidal neurons of mouse prefrontal cortex. In Fmr1 knockout (KO) mice, the D1‐mediated facilitation of evoked IPSCs is absent whereas the initial suppression is unaltered. Downstream mechanisms of the D1‐mediated facilitation (i.e. cAMP‐dependent facilitation) persists in Fmr1 KO neurons; however, there is a decrease in D1 receptor protein in the Fmr1 KO tissues. These results indicate the dopamine‐dependent modulation of inhibition is dampened in Fmr1 KO animals, which could produce a relative hyperexcitability of neural circuitry within decision‐making regions of the prefrontal cortex in fragile X syndrome.Abstract  Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive‐compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long‐lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1‐type receptors seen in wild‐type mice; however, such enhancement is absent in the Fmr1 knock‐out ( Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.