Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson’s disease (PD) as well as with the development ofl-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned,l-DOPA-treated dyskinetic, andl-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopamine-denervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved inl-DOPA-induced dyskinesia.

To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mg/kg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40- and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3–CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and short-term potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K ⁺ -evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy.

Declines in physical performance and cognition are commonly observed in older adults. The geroscience paradigm posits that a set of processes and pathways shared among age-associated conditions may also serve as a molecular explanation for the complex pathophysiology of physical frailty, sarcopenia, and cognitive decline. Mitochondrial dysfunction, inflammation, metabolic alterations, declines in cellular stemness, and altered intracellular signaling have been observed in muscle aging. Neurological factors have also been included among the determinants of sarcopenia. Neuromuscular junctions (NMJs) are synapses bridging nervous and skeletal muscle systems with a relevant role in age-related musculoskeletal derangement. Patterns of circulating metabolic and neurotrophic factors have been associated with physical frailty and sarcopenia. These factors are mostly related to disarrangements in protein-to-energy conversion as well as reduced calorie and protein intake to sustain muscle mass. A link between sarcopenia and cognitive decline in older adults has also been described with a possible role for muscle-derived mediators (i.e., myokines) in mediating muscle–brain crosstalk. Herein, we discuss the main molecular mechanisms and factors involved in the muscle–brain axis and their possible implication in cognitive decline in older adults. An overview of current behavioral strategies that allegedly act on the muscle–brain axis is also provided.