Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1epileptic encephalopathy

Dynamin-1 is a large GTPase with an obligatory role in synaptic vesicle endocytosis at mammalian nerve terminals. Heterozygous missense mutations in the dynamin-1 gene (DNM1) cause a novel form of epileptic encephalopathy, with pathogenic mutations clustering within regions required for its essential GTPase activity. We reveal the most prevalent pathogenic DNM1 mutation, R237W, disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. To determine how this mutation impacted cell, circuit and behavioural function, we generated a mouse carrying the R237W mutation. Neurons from heterozygous mice display dysfunctional endocytosis, in addition to altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes are corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates endocytosis. Here, we demonstrate a credible link between dysfunctional endocytosis and epileptic encephalopathy, and importantly reveal that synaptic vesicle recycling may be a viable therapeutic target for monogenic intractable epilepsies.<br/

The malleable brain: plasticity of neural circuits and behavior: A review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation (LTP) and long-term depression (LTD) respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by LTP and LTD, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.Fil: Schaefer, Natascha. University of Wuerzburg; AlemaniaFil: Rotermund, Carola. University of Tuebingen; AlemaniaFil: Blumrich, Eva Maria. Universitat Bremen; AlemaniaFil: Lourenco, Mychael V.. Universidade Federal do Rio de Janeiro; BrasilFil: Joshi, Pooja. Robert Debre Hospital; FranciaFil: Hegemann, Regina U.. University of Otago; Nueva ZelandaFil: Jamwal, Sumit. ISF College of Pharmacy; IndiaFil: Ali, Nilufar. Augusta University; Estados UnidosFil: García Romero, Ezra Michelet. Universidad Veracruzana; MéxicoFil: Sharma, Sorabh. Birla Institute of Technology and Science; IndiaFil: Ghosh, Shampa. Indian Council of Medical Research; IndiaFil: Sinha, Jitendra K.. Indian Council of Medical Research; IndiaFil: Loke, Hannah. Hudson Institute of Medical Research; AustraliaFil: Jain, Vishal. Defence Institute of Physiology and Allied Sciences; IndiaFil: Lepeta, Katarzyna. Polish Academy of Sciences; ArgentinaFil: Salamian, Ahmad. Polish Academy of Sciences; ArgentinaFil: Sharma, Mahima. Polish Academy of Sciences; ArgentinaFil: Golpich, Mojtaba. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Nawrotek, Katarzyna. University Of Lodz; ArgentinaFil: Paid, Ramesh K.. Indian Institute of Chemical Biology; IndiaFil: Shahidzadeh, Sheila M.. Syracuse University; Estados UnidosFil: Piermartiri, Tetsade. Universidade Federal de Santa Catarina; BrasilFil: Amini, Elham. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Pastor, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Wilson, Yvette. University of Melbourne; AustraliaFil: Adeniyi, Philip A.. Afe Babalola University; NigeriaFil: Datusalia, Ashok K.. National Brain Research Centre; IndiaFil: Vafadari, Benham. Polish Academy of Sciences; ArgentinaFil: Saini, Vedangana. University of Nebraska; Estados UnidosFil: Suárez Pozos, Edna. Instituto Politécnico Nacional; MéxicoFil: Kushwah, Neetu. Defence Institute of Physiology and Allied Sciences; IndiaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Turner, Anthony J.. University of Leeds; Reino Unid