Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits. Here, we have investigated motor skill learning and its synaptic correlates in the fmr1 knock-out (KO) mouse. We find that fmr1 KO mice have impaired motor skill learning of a forelimb-reaching task, compared with their wild-type (WT) littermate controls. Electrophysiological recordings from the forelimb region of the primary motor cortex demonstrated reduced, training-induced synaptic strengthening in the trained hemisphere. Moreover, long-term potentiation (LTP) is impaired in the fmr1 KO mouse, and motor skill training does not occlude LTP as it does in the WT mice. Whereas motor skill training induces an increase of synaptic AMPA-type glutamate receptor subunit 1 (GluA1), there is a delay in GluA1 increase in the trained hemisphere of the fmr1 KO mice. Using transcranial in vivo multiphoton microscopy, we find that fmr1 KO mice have similar spine density but increased dendritic spine turnover compared with WT mice. Finally, we report that motor skill training-induced formation of dendritic spines is impaired in fmr1 KO mice. We conclude that FMRP plays a role in motor skill learning and that reduced functional and structural synaptic plasticity might underlie the behavioral deficit in the fmr1 KO mouse.

We previously demonstrated that monocyte-macrophage based drug delivery can be applied to a spectrum of infectious, neoplastic, and degenerative disorders. In particular, bone marrow-derived macrophages (BMM) loaded with nano formulated catalase, “nanozyme”, were shown to attenuate neuro inflammation and nigrostriatal degeneration in rodent models of Parkinson’s disease (PD). Nonetheless, the pharmacokinetics and biodistribution of BMM-incorporated nanozyme has not been explored. To this end, we now demonstrate that BMM, serving as a “depot” for nanozyme, increased area under the curve(AUC), half-life, and mean residence time in blood circulation of the protein when compared to the nanozyme administered alone. Accordingly, bioavailability of the nanozyme for the brain, spleen, kidney, and liver was substantially increased. Importantly, nanozyme-loaded BMM targeted diseased sites and improved transport across the blood brain barrier. This was seen specifically in affected brain subregions in models of PD. Engaging natural immune cells such as monocyte-macrophages as drug carriers provides a new perspective for therapeutic delivery for PD and also likely a range of other inflammatory and degenerative diseases.

Experimental models and experimental designsAll procedures were approved by the Institutional Care and Use Committee of the University of Pennsylvania and Eli Lilly and Company. Adult male C57BL/6 mice (Taconic) weighing ~20g at arrival (n=84) were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Mice were individually housed in standard cages with ad libitum access to chow diet (2014, Research Diets) and tap water for all experiments except when noted.Adult male Sprague-Dawley rats (Charles River) weighing ~250-270 g (n=93) at arrival were housed under a 12-hour:12-hour light/dark cycle in a temperature-and humidity-controlled vivarium. Rats were individually housed in hanging wire-bottomed cage with ad libitum access to chow diet (Purina Lab Diet 5001), tap water and also had ad libitum access to kaolin pellets (Research Diets, K50001). Rats were exposed to kaolin for at least 5 days prior to measuring kaolin consumption in pica testing.Adult male shrews (Suncus murinus) weighing ~50-80 g (n=118 total), where bred and

Opioid use disorder (OUD) affects millions of people worldwide and the risk of developing the disorder has a significant genetic component according to twin and family studies. Identification of the genetic variants underlying this inherited risk has focused on two different methods: candidate gene studies and genome-wide association studies (GWAS). The most studied candidate genes have included the mu-opioid receptor (OPRM1), the delta-opioid receptor (OPRD1), the dopamine D2 receptor (DRD2), and brain-derived neurotrophic factor (BDNF). Variants in these genes have been associated with relatively small, but reproducible, effects on OUD risk. More recently, GWAS have identified potential associations with variants in KCNG2, KCNC1, CNIH3, APBB2, and RGMA. In total the genetic associations identified so far explain only a small portion of OUD risk. GWAS of OUD is still in the early stages when compared to studies of other psychiatric disorders, such as schizophrenia, which have found many relevant variants with small effect sizes only after large meta-analyses. Substantial increases in cohort sizes will likely be necessary in the OUD field to achieve similar results. In addition, it will be important for future studies of OUD to incorporate rare variants, epigenetics, and gene × environment interactions into models in order to better explain the observed heritability.