4-aminopiperidine and Disease-Models--Animal

Despite the availability of multiple antiepileptic drugs (AED), failure to adequately control seizures is a challenge for approximately one third of epilepsy patients, and new therapies with a differentiated mechanism of action are needed. The neuroactive steroid, SGE-516, is a positive allosteric modulator of both gamma- and delta-containing GABA

Topics: Action Potentials; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Electroshock; Fragile X Mental Retardation Protein; gamma-Aminobutyric Acid; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Knockout; Pentylenetetrazole; Piperidines; Potassium Channel Blockers; Pregnanolone; Rats; Rats, Sprague-Dawley; Seizures

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS.

Topics: Animals; Animals, Newborn; Calcium; Disease Models, Animal; Electric Stimulation; Excitatory Postsynaptic Potentials; Fragile X Mental Retardation Protein; Fragile X Syndrome; GABA Antagonists; Hippocampus; In Vitro Techniques; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Neural Inhibition; Neuronal Plasticity; Patch-Clamp Techniques; Phosphinic Acids; Piperidines; Potassium Channel Blockers; Presynaptic Terminals; Propanolamines; Sodium Channel Blockers; Synapses; Tetraethylammonium; Tetrodotoxin; Time Factors