Both NMDA hypofunction and dopamine hyperfunction have been implicated in Schizophrenia. Moreover, the hippocampal region appears to be involved in the disease, perhaps because of aberrant novelty detection processes in the CA1 region. These novelty detection processes may depend on predictions arriving at CA1 from CAS via the Schaffer collaterals (SC) and sensory reality arriving directly from cortex via the perforant path (PP). It is therefore important to understand dopamine and NMDAR function in CA1, to elucidate the ways in which they contribute to pathway interactions, and to test the hypothesis that these pathway interactions indeed underlie a novelty detection process. Aim 1 seeks to understand the role of dopamine/NMDAR interactions at the SC and PP. Preliminary evidence indicates that D1 modulation can affect the NMDA conductance through a postsynaptic process, that the NMDA subunits are different in the two pathways and that D1 modulation may depend on NMDA subunit composition. This line of investigation will be continued and extended to D2 modulation. The ability to excite individual synapses using two-photon uncaging of glutamate will allow the first study of dopaminergic modulation at single dendritic spines. It will thus be possible to test whether this modulation is heterogeneous at the single spine level. Aim 2 utilizes both in vivo and in vitro approaches to test the hypothesis that pathway interactions perform a novelty detection process. Whole cell recording will be used to understand the biophysics of pathway interaction and the role of NMDAR and dopaminergic modulation in this process. Preliminary work suggests that pathway interactions can lead to supra-linear dendritic responses and that these are dependent on the NMDAR function. However, other work indicates that naturally occurring processes mediated by GABA conductances and lh can prevent (brake) the supralinearity. Experiments will be conducted to determine whether there are pathway timing conditions or neuromodulatory conditions in which the effectiveness of the brake is minimized. A supralinear response generated by an NMDA spike would be a candidate biophysical response to mediate novelty detection (a match signal). The role of dopamine in modulating these pathways (as studied in Aim 1) will also be examined. A critical need in understanding the pathway interactions studied in vitro is to obtain data about the CA1 computations that occur in vivo. In collaboration with the Center member, Howard Eichenbaum, recordings will be made from the CA1 region during the presentation of novel sequences. Multiple tetrodes will be used to test whether CA1 is a site of novelty detection, as proposed on theoretical grounds. Together these lines of investigation will help to integrate events spanning across multiple levels and elucidate how molecular defects in the NMDA and dopamine system could contribute to symptoms of schizophrenia.