Experience-dependent plasticity at excitatory synapses within dopamine neurons of the ventral tegmental area (VTA), a key region for a broad range of motivated behaviors, is thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Synaptic plasticity 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. We suspected that this peculiar synaptic phenotype is capable of producing perturbations to the physiological expression of general associative learning and memory. To address the latter questions we designed behavioral experiments looking for associative learning related to aversion: fear conditioning test. At this point my preliminary data suggest that cKO animals exhibited a propensity to learn a fearful experience (fear conditioning) compared to their respective littermates controls.
| 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 |
