Prenatal nicotine exposure alters postsynaptic AMPA receptors and glutamate neurotransmission within the laterodorsal tegmentum (LDT) of juvenile mice

Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

“…This process has been shown to occur in the LDT following postnatal chronic exposure to cocaine (Kaneda, 2019). Our studies provide further support that intrinsic plasticity can be altered by experience, as we showed that a form of intrinsic plasticity is engendered by early-life exposure to nicotine, as reflected in alterations in membrane properties and action potential kinetics of LDT neurons in the PNE (Polli and Kohlmeier, 2018). Further, PNE treatment was associated with lower activity-dependent intracellular calcium rises in putative cholinergic LDT cells of juvenile mice, assessed by single-photon calcium imaging of neurons activated by high current injection (Polli and Kohlmeier, 2018), which was an effect attributed to a reduced functionality of voltage-gated calcium channels (VGCCs).…”

“…Interestingly, a higher functional presence of the immature CP-AMPAR seems to be a common brain outcome following exposure to drugs of abuse, and has been reported after postnatal administration of cocaine, morphine, and ethanol (Bellone and Luscher, 2006;Billa et al, 2010;Purgianto et al, 2013;Hausknecht et al, 2015). We have recently reported that PNE is associated with electrophysiological alterations in AMPAR-mediated signaling in the LDT, that were suggestive of an enhanced functional presence of CP-AMPARs among putative cholinergic neurons within the LDT nucleus that was confirmed by a demonstrated greater action of the pharmacological blocker of CP-AMPAR, NASPM, on AMPARmediated currents in PNE LDT neurons (Polli and Kohlmeier, 2018). Thus, we concluded that PNE treatment was associated with enhanced functional presence of the immature CP-AMPAR within the large LDT neurons of juvenile mice, resulting in enhanced AMPAR-mediated signaling responsiveness, including a higher amplitude of mEPSCs.…”

“…In our work, we have found a reduced frequency of mEPSCs in putative cholinergic LDT neurons associated with PNE treatment, suggesting a lower probability of activity-independent glutamate release from presynaptic terminals within this nucleus (Polli and Kohlmeier, 2018). A more direct assay of presynaptic release employs a paired pulse stimulation protocol resulting in two evoked EPSCs (eEPSCs), elicited by an external electrode placed nearby a patch-clamped, recorded neuron.…”

“…This phenomenon is called shortterm facilitation, and can be mechanistically explained by the residual calcium hypothesis, in which calcium at presynaptic terminals resulting from the first stimulation builds up with that from the second, leading to a potentiation in the number of vesicles released from presynaptic terminals, and an enhanced postsynaptic response during the second stimulation, which reveals a reduced probability of glutamate release at the first stimulus (Malinow and Malenka, 2002). By having employed this protocol in PNE male juveniles, paired pulse facilitation was found in putative cholinergic LDT neurons, which was reflected as reduced glutamate neurotransmission within these cells (Polli and Kohlmeier, 2018). These findings are consistent with the interpretation that PNE treatment results in reductions in glutamatergic drive directed to postsynaptic cholinergic neurons within the LDT, which corroborates findings of a smaller frequency of mEPSCs seen in the PNE.…”

Connections of the laterodorsal tegmental nucleus with the habenular‐interpeduncular‐raphe system

“…A functional role for cholinergic LDTg inputs to IP in mechanisms of reward/aversion has not been specified yet. Even so, there is electrophysiological evidence that nicotine enhances the excitability of cholinergic and noncholinergic LDTg neurons (Ishibashi, Leonard, & Kohlmeier, ; Polli & Kohlmeier, ). Thus, it is well conceivable that neuroplasticity in cholinergic IP‐projecting LDTg neurons is involved in the regulation of reward circuitry, as it has been shown by optogenetic approaches for cholinergic and glutamatergic LDTg projections targeting the VTA (Dautan et al, ; Kaneda, ; Lammel et al, ; Steidl, Wang, Ordonez, Zhang, & Morales, ).…”