No abstract

Cholinergic neurons in the basal forebrain project heavily to the main olfactory bulb, the first processing station in the olfactory pathway. The projections innervate multiple layers of the main olfactory bulb and strongly influence odor discrimination, detection, and learning. The precise underlying circuitry of this cholinergic input to the main olfactory bulb remains unclear, however. Here, we identify a specific basal forebrain cholinergic projection that innervates select neurons concentrated in the internal plexiform layer of the main olfactory bulb. Optogenetic activation of this projection elicits monosynaptic nicotinic and GABAergic currents in glomerular layer-projecting interneurons. Additionally, we show that the projection co-expresses markers for GABAergic neurotransmission. The data thus implicate neurotransmitter co-transmission in the basal forebrain regulation of this inhibitory olfactory microcircuit.

The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson's disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (ϳ70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. L-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson's disease and related disorders.Key words: acetylcholine; basal ganglia; dopamine; glutamate; Parkinson's; VGLUT3 Significance StatementDopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson's disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson's disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to L-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson's disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson's disease and potentially other basal-ganglia-related disorders.

The lateral superior olive (LSO) integrates excitatory inputs driven by sound arriving at the ipsilateral ear with inhibitory inputs driven by sound arriving at the contralateral ear in order to compute interaural intensity differences needed for localizing high-frequency sound sources. Specific mechanisms necessary for developmental refinement of the inhibitory projection, which arises from the medial nucleus of the trapezoid body (MNTB), have only been partially deciphered. The demonstration that immature MNTB-LSO synapses release glutamate has led to a model in which early glutamate neurotransmission plays a major role in inhibitory plasticity. We used whole cell electrophysiology in acute auditory brain stem slices of neonatal rats to examine glutamatergic transmission in the developing MNTB-LSO pathway. Unexpectedly, AMPA receptor (AMPAR)-mediated responses were prevalent at the earliest ages. We found a salient developmental profile for NMDA receptor (NMDAR) activation, described both by the proportion of total glutamate current and by current durations, and we found evidence for distinct release probabilities for GABA/glycine and glutamate in the MNTB-LSO pathway. The developmental profile of NMDAR is consistent with the possibility that the inhibitory MNTB-LSO pathway experiences a sensitive period, driven by cochlear activity and mediated by GluN2B-containing NMDARs, between postnatal days 3 and 9. Differing neurotransmitter release probabilities could allow the synapse to switch between GABA/glycinergic transmission and mixed glutamate/GABA/glycinergic transmission in response to changing patterns of spiking activity.