fMRI study of the role of glutamate NMDA receptor in the olfactory adaptation in rats: Insights into cellular and molecular mechanisms of olfactory adaptation.

Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic terminals due to glutamate over-replenishment during the interruption of odor stimulation. Furthermore, with blockage of the adaptations, the data reveal that orbital, medial & prefrontal, and cingulate cortices (OmPFC) are involved in the olfactory processing.

Muscarinic Receptors, from Synaptic Plasticity to its Role in Network Activity.

Acetylcholine acting via metabotropic receptors plays a key role in learning and memory by regulating synaptic plasticity and circuit activity. However, a recent overall view of the effects of muscarinic acetylcholine receptors (mAChRs) on excitatory and inhibitory long-term synaptic plasticity and on circuit activity is lacking. This review focusses on specific aspects of the regulation of synaptic plasticity and circuit activity by mAChRs in the hippocampus and cortex. Acetylcholine increases the excitability of pyramidal neurons, facilitating the generation of dendritic Ca2+-spikes, NMDA-spikes and action potential bursts which provide the main source of Ca2+ influx necessary to induce synaptic plasticity. The activation of mAChRs induced Ca2+ release from intracellular IP3-sensitive stores is a major player in the induction of a NMDA independent long-term potentiation (LTP) caused by an increased expression of AMPA receptors in hippocampal pyramidal neuron dendritic spines. In the neocortex, activation of mAChRs also induces a long-term enhancement of excitatory postsynaptic currents. In addition to effects on excitatory synapses, a single brief activation of mAChRs together with short repeated membrane depolarization can induce a long-term enhancement of GABA A type (GABAA) inhibition through an increased expression of GABAA receptors in hippocampal pyramidal neurons. By contrast, a long term depression of GABAA inhibition (iLTD) is induced by muscarinic receptor activation in the absence of postsynaptic depolarizations. This iLTD is caused by an endocannabinoid-mediated presynaptic inhibition that reduces the GABA release probability at the terminals of inhibitory interneurons. This bidirectional long-term plasticity of inhibition may dynamically regulate the excitatory/inhibitory balance depending on the quiescent or active state of the postsynaptic pyramidal neurons. Therefore, acetylcholine can induce varied effects on neuronal activity and circuit behavior that can enhance sensory detection and processing through the modification of circuit activity leading to learning, memory and behavior.