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Recent data demonstrate weaker gamma-aminobutyric acid (GABA)-ergic inhibition in ventral (VH) compared with dorsal (DH) hippocampus. Therefore, we examined possible differences regarding the GABAA receptors between VH and DH as follows: 1) the expression of the GABAA receptor subunits (alpha1/2/4/5, beta1/2/3, gamma2, delta) mRNA and protein and 2) the quantitative distribution and kinetic parameters of [3H] muscimol (GABAA receptor agonist) binding. VH compared with DH showed: 1) lower levels for alpha1, beta2, gamma2 but higher levels for alpha2 and beta1 subunits in CA1, CA2, and CA3, the differences being more pronounced in CA1 region; in the CA1 region, the mRNA levels of alpha5 were higher, whereas those of alpha4 subunit were slightly lower; in dentate gyrus, the mRNA levels of alpha4, beta3, and delta subunits were significantly lower, presumably suggesting a lower expression of the alpha4/beta3/delta receptor subtype; and 2) lower levels of [3H]muscimol binding, with the lowest value observed in CA1, apparently resulting from weaker binding affinity, insofar as the KD values were higher in VH, whereas the Bmax values were similar between DH and VH. The differences in the subunit expression and the lower affinity of GABAA receptor binding observed predominantly in the CA1 region of VH suggest that the alpha1/beta2/gamma2 GABAA receptor subtype dominates in DH, and the alpha2/beta1/gamma2 subtype prevails in VH. This could underlie the lower GABAA-mediated inhibition observed in VH and, to some extent, explain 1) the higher liability of VH for epileptic activity and 2) the differential involvement of DH and VH in cognitive and emotional processes.

A great body of evidence points toward a functional interaction between metabotropic glutamate 5 receptors (mGluR5) and NMDA receptors (NMDAR) that enhances synaptic plasticity and cognition. However, the molecular mechanism underlying this interaction remains unclear. Here, we show that co-activation of mGluR5 and NMDAR in hippocampal slices synergistically leads to a robust phosphorylation of NR2B (Tyr1472), which is Src kinase dependent and is enabled by endogenous adenosine acting on A 2A receptors. As it is well known, NR2B (Tyr1472) phosphorylation anchors NR2B-containing NMDARs to the surface of post-synaptic membranes, preventing their internalization. This is supported by our electrophysiological experiments showing that co-activation of mGluR5 and NMDARs robustly enhances NMDAR-dependent neuronal excitability recorded in CA1 hippocampal region, which temporally coincides with the robust increase in NR2B (Tyr1472) phosphorylation, depends on Src kinases and is also permitted by A 2A receptors. Thus, we strongly suggest that NR2B (Tyr1472) phosphorylation constitutes, at least to some extent, the molecular mechanism underlying the mGluR5-mediated enhancement of NMDAR-dependent responses, which is modulated by A 2A receptors. A better understanding of the molecular basis of mGluR5/NMDAR interaction would elucidate their role in synaptic plasticity processes as well as in pathological conditions.

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