ABSTRACT
Fmr1 knock-out (ko) mice display key features of fragile X syndrome (FXS), including delayed dendritic spine maturation and FXS-associated behaviors, such as poor socialization, obsessive-compulsive behavior, and hyperactivity. Here we provide conclusive evidence that matrix metalloproteinase-9 (MMP-9) is necessary to the development of FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9 rescued key aspects of Fmr1 deficiency, including dendritic spine abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant behaviors in open field and social novelty tests. Remarkably, MMP-9 deficiency also corrected non-neural features of Fmr1 deficiency-specifically macroorchidism-indicating that MMP-9 dysregulation contributes to FXS-associated abnormalities outside the CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E phosphorylation seen in Fmr1 ko mice, which are also associated with other autistic spectrum disorders. These findings establish that MMP-9 is critical to the mechanisms responsible for neural and non-neural aspects of the FXS phenotype.
Subject(s)
Disease Models, Animal , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Matrix Metalloproteinase 9/deficiency , Matrix Metalloproteinase 9/genetics , Animals , Animals, Newborn , Cells, Cultured , Fragile X Syndrome/pathology , Male , Mice , Mice, 129 Strain , Mice, Knockout , PhenotypeABSTRACT
CoA (coenzyme A) is an essential cofactor that is involved in many metabolic processes. CoA is derived from pantothenate in five biosynthetic reactions. The CoA biosynthetic pathway is regulated by PanKs (pantothenate kinases) and four active isoforms are expressed in mammals. The critical physiological functions of the PanKs are revealed by systematic deletion of the Pank genes in mice.
Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/metabolism , Animals , Coenzyme A/metabolism , Mice , Mitochondria/microbiology , Phosphotransferases (Alcohol Group Acceptor)/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolismABSTRACT
Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability, with behaviors characteristic of autism. Symptoms include abnormal social behavior, repetitive behavior, communication disorders, and seizures. Many symptoms of FXS have been replicated in the Fmr1 knockout (KO) mice. Whether Fmr1 KO mice exhibit vocal communication deficits is not known. By recording ultrasonic vocalizations (USV) produced by adult male mice during mating, we show that USV calling rate (number of calls/second) is reduced in Fmr1 KO mice compared to WT controls. The WT control and Fmr1 KO groups did not differ in other aspects of mating behavior such as time spent sniffing, mounting, rooting and without contact. Acoustic properties of calls such as mean frequency (in kHz), duration and dynamic range of frequencies were not different. This indicates a specific deficit in USV calling rate in Fmr1 KO mice. Previous studies have shown that treatment of Fmr1 KO mice with minocycline for 4weeks from birth can alleviate some behavioral symptoms. Here we tested if minocycline also reversed vocalization deficits in these mice. Calling rate increased and was similar to WT controls in adult Fmr1 KO mice treated with minocycline for four weeks from birth (P0-P28). All acoustic properties measured were similar in treated and untreated WT control mice indicating minocycline effects were specific to vocalizations in the Fmr1 KO mice. These data suggest that mating-related USVs are robust and relevant biomarkers of FXS, and that minocycline treatment is a promising avenue for treatment of FXS symptoms.
Subject(s)
Fragile X Syndrome/drug therapy , Fragile X Syndrome/psychology , Minocycline/pharmacology , Sexual Behavior, Animal/drug effects , Vocalization, Animal/drug effects , Animals , Disease Models, Animal , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/physiopathology , Male , Mice , Mice, KnockoutABSTRACT
Dendritic spines are dynamic structures that accommodate the majority of excitatory synapses in the brain and are influenced by extracellular signals from presynaptic neurons, glial cells, and the extracellular matrix (ECM). The ECM surrounds dendritic spines and extends into the synaptic cleft, maintaining synapse integrity as well as mediating trans-synaptic communications between neurons. Several scaffolding proteins and glycans that compose the ECM form a lattice-like network, which serves as an attractive ground for various secreted glycoproteins, lectins, growth factors, and enzymes. ECM components can control dendritic spines through the interactions with their specific receptors or by influencing the functions of other synaptic proteins. In this review, we focus on ECM components and their receptors that regulate dendritic spine development and plasticity in the normal and diseased brain.