Background
First described in 1965, children with Angelman syndrome (AS, DOID_1932) present clinically with physical features such as microcephaly and a puppet like gait as wells as profound developmental delays and little vocal communication ability. While these patients exhibit a happy demeanor and easily provoked laughter, this syndrome also consists of other manifestations including hyper-excitability, poor motor function, and delays in adaptive behaviors. Furthermore, patients with AS exhibit EEG patterns specific to the syndrome, and when present in the appropriate clinical context, help in diagnosing the syndrome earlier. Finally, 90% of children diagnosed with AS suffer from seizure of various types and severity.
Angelman syndrome is unique in that nearly all cases result from the disruption of a single gene, UBE3A. Previous research in both the AS mouse model and humans with AS show no gross morphology changes in brain. However, the absence of the protein product, UBE3A, a E3 ubiquitin ligase, results in the accumulation of regulatory proteins, such as arc and ephexin 5 in the postsynaptic density, which is believed to cause abnormal dendritic spine morphology (filopodial) and density in hippocampal pyramidal neurons leading to aberrant synaptic function. These alterations in spine morphology and synaptic function in neurons provides an explanation for the severe behavioral and cognitive manifestations of the syndrome. Our laboratory has recently reported the application of Reelin, a protein shown to increase dendritic spine density, enhanced cognition in a mouse model. Further, other researchers have recently reported the recovery of the cognitive and behavioral deficits associated with AS and even the commencement of UBE3A protein production when certain therapeutics such as UBE3A viral vectors and topoisomerase inhibitors were applied. It stands to reason then, a therapeutic with the ability to normalize the aberrant synaptic function underlying AS could ameliorate the severity of symptoms.
Minocycline hydrochloride (MC) is a small (495 kDa), lipophilic, second-generation tetracycline antibiotic medication that readily crosses the blood brain barrier. These characteristics allow minocycline to penetrate the central nervous system more readily than other members of the tetracycline family. As with the aforementioned therapies, minocycline has been shown to recover synaptic dysfunction through the modulation of dendritic spine structure by reducing the activity of matrix metalloproteinases. Previous research has shown the incubation of neuronal cultures with MMP-9 altered dendritic spine shape and number. Moreover, increases in both protein level and activity of the MMP's occurs in models of epilepsy, which is prevalent in the AS population. Further, minocycline changes the morphology of dendritic spines in hippocampal neurons from elongated (immature) to mushroom-shaped (mature), ultimately rescuing the synaptic defect and improving spatial memory.
Interestingly the application of minocycline has been shown to act on numerous other aspects of the CNS. The drug has been shown to be neuroprotective, anti-apoptotic, and anti-inflammatory. Beyond this, minocycline can positively alter the AMPA-type glutamate receptor, metabotropic glutamate receptor 1 and 5 and NMDA receptor function. Metabotropic glutamate receptors, AMPA receptors and NMDA receptors are known to be important in overall neuronal function and contribute to the synaptic plasticity defect in the AS mouse model.
Minocycline has also been used as a treatment of other human cognitive disorders. For example, when MC was administered to patients with Fragile X syndrome (FRX), significant behavioral improvement in the subscale scores of the Aberrant Behavior Checklist-Community, as well as the Visual Analog Scale and Clinical Global Impressions Scale scores were reported with only minor adverse effects observed. Studies of the drug's effect on degenerative neuropathology (e.g., Alzheimer's and Parkinson's disease, Amyotrophic Lateral Sclerosis) have shown the administration of minocycline reduces the severity and progression of disease and, in some cases, prolongs the lifespan of animal models.
Preclinical electrophysiological studies were carried out in a mouse model of AS (RRID:IMSR_JAX:004477) after 21 days of minocycline treatment. We found a full recovery of the synaptic plasticity defect normally observed in the AS mouse model (Figure 1). We, and others, have shown a reduction in synaptic plasticity in the hippocampus, cerebellum and visual cortex in the AS mice. Therefore, recovery of the synaptic plasticity defect was a significant finding for this therapeutic.
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Figure 1.
Minocycline restores the synaptic plasticity defect in the AS mouse model. 3-month-old UBE3A maternal deficient (AS) mice show increase in long-term potentiation (LTP) after 21 days of treatment with minocycline. Field extracellular postsynaptic potentials (fEPSPs) were recorded and their slopes are conveyed as a percentage of the pre-theta burst stimulation (TBS) baseline. Representative traces before (bold) and 30 minutes after TBS are shown for saline treated (control) and minocycline treated AS mice.
The precise mechanism of minocycline, beyond its antibacterial mechanism, is unknown. However, this has not precluded the investigation of minocycline (with associated benefit) on human neurological diseases such as Alzheimer's, Parkinson's, Stroke, traumatic brain injuries and Fragile X syndrome. The results of the above mentioned studies led us to posit that administering minocycline to patients with Angelman syndrome may ameliorate the central nervous system symptoms associated with the syndrome and improve behavioral performance. Here, we report the changes in symptom severity, cognition, and adaptive behavior after a sample of 25 children with Angelman syndrome were administered minocycline for 8 weeks.