Disruption of GABA(A) receptors on GABAergic interneurons leads to increased oscillatory power in the olfactory bulb network

Synchronized neural activity is believed to be essential for many CNS funct ions, including neuronal development, sensory perception, and memory format ion. In several brain areas GABA(A) receptor-mediated synaptic inhibition i s thought to be important for the generation of synchronous network activit y. We have used GABA(A) receptor beta3 subunit deficient mice (beta3-/-) to study the role of GABAergic inhibition in the generation of network oscill ations in the olfactory bulb (OB) and to reveal the role of such oscillatio ns in olfaction. The expression of functional GABA(A) receptors was drastic ally reduced (>93%) in beta3-/- granule cells, the local inhibitory interne urons of the OB. This was revealed by a large reduction of muscimol-evoked whole-cell current and the total current mediated by spontaneous, miniature inhibitory postsynaptic currents (mIPSCs). In beta3-/- mitral/tufted cells (principal cells), there was a two-fold increase in mIPSC amplitudes witho ut any significant change in their kinetics or frequency. In parallel with the altered inhibition, there was a significant increase in the amplitude o f theta (80% increase) and gamma (178% increase) frequency oscillations in beta3-/- OBs recorded in vivo from freely moving mice. In odor discriminati on tests, we found beta3-/- mice to be initially the same as, but better wi th experience than beta3+/+ mice in distinguishing closely related monomole cular alcohols. However, beta3-/- mice were initially better and then worse with practice than control mice in distinguishing closely related mixtures of alcohols. Our results indicate that the disruption of GABA(A) receptor- mediated synaptic inhibition of GABAergic interneurons and the augmentation of IPSCs in principal cells result in increased network oscillations in th e OB with complex effects on olfactory discrimination, which can be explain ed by an increase in the size or effective power of oscillating neural cell assemblies among the mitral cells of beta3-/- mice.