DIFFERENTIAL-EFFECTS OF HISTAMINE ON THE N-METHYL-D-ASPARTATE CHANNELIN HIPPOCAMPAL SLICES AND CULTURES

The effect of histamine on N-methyl-D-aspartate currents was investiga ted in pyramidal neurons in the CA1 region of acute hippocampal slices from juvenile rats. The objective was to compare histamine effects in the slice with those previously reported in acutely dissociated and c ultured hippocampal neurons. Micromolar concentrations of histamine ha d no effect on N-methyl-D-aspartate-mediated excitatory postsynaptic c urrents in the slice, in contrast to the large enhancement seen in cul ture under identical conditions. However, millimolar concentrations of histamine blocked these currents both in the slice and in culture. Po ssible reasons for the lack of enhancement in the slice were explored as follows. (1) Histamine could not penetrate the slice or was already present at high concentrations inside the dice. This was tested by re cording N-methyl-D-aspartate currents elicited in outside-out patches pulled from the somas of CA1 slice neurons. Histamine still had no eff ect in patches, whereas the corresponding experiment for cultured neur ons showed robust enhancement. (2) Slices release an endogenous ligand that binds with high affinity to the histamine site on the N-methyl-D -aspartate receptor, blocking its activation. This was tested by super fusing cultures with supernatant from homogenized slice tissue. Histam ine enhancement was maintained in these cultures. (3) CA1 dices and cu ltures express different N-methyl-D-aspartate receptor subtypes. The r everse transcription-polymerase chain reaction technique was used to e xamine the expression of messenger RNA encoding N-methyl-D-aspartate r eceptor subunits in the two systems. No difference was found in the wh ole-tissue expression of messenger RNA for the NR2A, 2B or 2C subunits or for the eight known splice variants of the NR1 subunit. It is hypo thesized that the differential enhancing effect of histamine in slices and culture involves posttranslational modifications or other factors that modulate the N-methyl-D-aspartate receptor/ion channel according to its environment.