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 noveltydetection processes in the CA1 region. These novelty detection processes may depend on predictionsarriving at CA1 from CAS via the Schaffer collaterals (SC) and sensory reality arriving directly from cortex viathe perforant path (PP). It is therefore important to understand dopamine and NMDAR function in CA1, toelucidate the ways in which they contribute to pathway interactions, and to test the hypothesis that thesepathway interactions indeed underlie a novelty detection process.
Aim 1 seeks to understand the role ofdopamine/NMDAR interactions at the SC and PP. Preliminary evidence indicates that D1 modulation canaffect the NMDA conductance through a postsynaptic process, that the NMDA subunits are different in thetwo pathways and that D1 modulation may depend on NMDA subunit composition. This line of investigationwill be continued and extended to D2 modulation. The ability to excite individual synapses using two-photonuncaging of glutamate will allow the first study of dopaminergic modulation at single dendritic spines. It willthus be possible to test whether this modulation is heterogeneous at the single spine level.
Aim 2 utilizesboth in vivo and in vitro approaches to test the hypothesis that pathway interactions perform a noveltydetection process. Whole cell recording will be used to understand the biophysics of pathway interaction andthe role of NMDAR and dopaminergic modulation in this process. Preliminary work suggests that pathwayinteractions can lead to supra-linear dendritic responses and that these are dependent on the NMDARfunction. However, other work indicates that naturally occurring processes mediated by GABA conductancesand lh can prevent (brake) the supralinearity. Experiments will be conducted to determine whether there arepathway timing conditions or neuromodulatory conditions in which the effectiveness of the brake isminimized. A supralinear response generated by an NMDA spike would be a candidate biophysical responseto mediate novelty detection (a match signal). The role of dopamine in modulating these pathways (asstudied in Aim 1) will also be examined. A critical need in understanding the pathway interactions studied invitro is to obtain data about the CA1 computations that occur in vivo. In collaboration with the Centermember, Howard Eichenbaum, recordings will be made from the CA1 region during the presentation of novelsequences. Multiple tetrodes will be used to test whether CA1 is a site of novelty detection, as proposed ontheoretical grounds. Together these lines of investigation will help to integrate events spanning acrossmultiple levels and elucidate how molecular defects in the NMDA and dopamine system could contribute tosymptoms of schizophrenia.
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