The experiments outlined in this application are designed to address the role of the synaptic protein PSD-95 in the synaptic transmission and plasticity of excitatory synapses in the nucleus accumbens shell (NAc) and if these mechanisms underlie some of the effects of chronic drug exposure. Genetic manipulation via recombinant lentivirus will be used to acutely knock down or enhance expression of PSD-95 proteins in medium spiny neurons of the NAc shell in living wild type mice. Characteristics of basal excitatory synaptic transmission will be examined in infected vs uninfected neurons via whole cell patch clamp recording and pharmacological manipulation of acute NAc slices. The effects of PSD-95 depletion or enhancement upon synaptic plasticity in the NAc shell will be addressed by studying NMDAR dependant forms of LTD and LTP as well as endocannabinoid LTD in infected neurons. If time permits, in vivo manipulation of PSD-95 levels will also be combined with a chronic cocaine regimen in order to examine the contributions of this protein to the depression of synaptic strength seen in the NAc shell in response to long term drug exposure.
| Luu, Percy; Malenka, Robert C (2008) Spike timing-dependent long-term potentiation in ventral tegmental area dopamine cells requires PKC. J Neurophysiol 100:533-8 |
