Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3a(m-/p+)), recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3a(m-/p+) mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3a(m-/p+) mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3a(m-/p+) mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.
University of North Carolina, Chapel Hill, NC 27599-7545, USA.
Michael L
ML
Wallace
Alain C
AC
Burette
Richard J
RJ
Weinberg
Benjamin D
BD
Philpot
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D064032:Calbindin 2; D004558:Electric Stimulation; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000145:classification* / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*; D014793:Visual Cortex / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism
D064032:Calbindin 2; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D049452:Green Fluorescent Proteins; D013004:Somatostatin; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases