It is thought that schizophrenia involves dopamine hyperfunction and/or NMDAR hypofunction and that the hippocampus is a key site of aberrant information processing. Our recent work on the Schaffer collateral (sc) and perforant path (pp) inputs to CA1 hippocampal pyramidal cells shows that NMDAR-mediated synaptic transmission is decreased by dopamine. This is the first indication of a site in the hippocampus for dopamine/NMDAR interaction. The goal of this proposal is to investigate presynaptic and postsynaptic sites where the NMDAR is modulated by dopamine. Similar methods will be used to study how the NMDAR is affected by an endogenous antagonist that may be involved in schizophrenia. 1.
Specific Aim 1 investigates the dopaminergic modulation of the sc input. Preliminary data suggest that this a clear-cut case of a postsynaptic action of dopamine: paired-pulse facilitation is not changed and only the NMDAR component of the fEPSP is inhibited. This makes the sc input a good system in which to study the postsynaptic dopaminergic modulation at the subcellular level. Ca2+ entry via NMDAR channels into individual synaptic events. If the control is postsynaptic, dopamine should decrease the magnitude of Ca2+ entry when successful transmission occurs, but not affect the probability of transmission. Pharmacological studies will be done to determine which types of dopamine receptors are involved. The literature suggests that dopamine receptors might be present on subsets of spines. Thus, an interesting question in our studies will be whether only a subset of spines is effected by dopamine or whether they are uniformly affected. 2.
Specific Aim 2 investigates the action of dopamine on the pp synapses located in distal dendrites. D1 and D2 receptors are especially concentrated in the vicinity of the pp input. Dopamine strongly inhibits the pp fEPSP and increased paired-pulse facilitation, suggesting that the modulation is at least partially presynaptic. However, the NMDAR decrease was much stronger than the AMPA, so a postsynaptic modulation may also occur. Either D1 or D2 antagonists inhibited dopamine action, but only clozapine could block it completely. Moreover, the pp input has much larger NMDAR component of normal transmission than the sc. All this makes dopaminergic modulation of the pp of special relevance to understanding the information processing deficits in schizophrenia. The very distal position of the pp input, however, makes it virtually inaccessible for traditional biophysical studies. By separately studying the probability and size of individual NMDAR-mediated spine Ca2+ signals, we will be able to separately study the presynaptic and postsynaptic components of dopaminergic modulation. We can then study which dopamine receptors are responsible for each action. 3.
Specific Aim 3 analyzes N-acetylaspartyl-glutamate (NAAG) modulation of the PP and the sc inputs. Initial studies w2ill use extracellular field recording methods. NAAG is known to act via the inhibition of NMDAR and/or activation of mGluR3 receptors. There are reasons to believe that NAAG might differently affect the sc and pp inputs. First, the NMDAR component is larger in the pp that in the sc. Second, the literature suggests that mGlur3 receptors are presynaptic on the pp but not the sc fibers. We will compare the magnitude of the effect of NAAG at sc and pp synapses and use electrophysiological and optical methods to determine whether the effects are presynaptic, postsynaptic or both.
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