Synaptic plasticity involves several orchestrated changes of synaptic efficacy supporting experience-dependent modifications of brain function, physiological foundations of learning and memory. The latter process is mainly described by long-term potentiation (LTP) and depression (LTD) of excitatory synaptic transmission, that are widespread phenomena within the mammalian brain (Malenka and Bear ; 2004). The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the fine regulation of synaptic activity reflected in LTP and LTD. The cellular events underlying this fundamental processes occurring into DA neurons of the VTA are still poorly understood. To dissect out the functional significance of synaptic plasticity (LTP and LTD) within dopaminergic neurons of the VTA we developed a new mouse line carrying a conditional deletion of the AAA+ ATPase Thorase protein in a DATcre dependent fashion. AAA+ ATPase Thorase protein mediates, in an ATPase-dependent manner, the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex (Zhang et al. 2011). Following genetic deletion of Thorase protein in DATcre expressing cells, the internalization of AMPAR is substantially reduced, leading to several perturbations of synaptic plasticity. My preliminary data suggest that DATcre x Thorase KO mice display reduced LTD and enhanced AMPA/NMDA ratio. This findings parallels and increased amplitude of mEPSCs for DATcrexThorase while the amplitude of mIPSCs is unaffected. Surprisingly, the impact of this synaptic configuration at the behavioral level is quite remarkable. We tested our animals with a fear conditioning paradigm, an associative learning and memory essay. We discovered that cKO animals exhibited a propensity to learn from a fearful experience (fear conditioning) compared to their respective littermates controls. It is tempting to speculate that a rigid synaptic state within DA neurons residing into the VTA is affecting the way animals cope with stressful events. This scientific project is now translating into a clinical direction since our collaborators Ted and Valina Dawson at Johns Hopkins University discovered 3 different point mutations of Thorase protein into families of Ashkenazi Jewish origin were schizophrenia cases were recurrent. We are now taking advantage of mouse genetics and electrophysiology to understand, in the mouse model, the molecular underpinnings of the observed point mutations at the functional level.
| Tejeda, Hugo A; Wu, Jocelyn; Kornspun, Alana R et al. (2017) Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity. Neuron 93:147-163 |
