The Nitric Oxide (NO) Signaling Pathway Regulates Pre- and Postsynaptic Mechanisms Following Long-Term Potentiation (LTP) Induction at Thalamo-Amygdala Synapses

Long-term potentiation (LTP) induction in the synapse projecting from auditory thalamus to lateral amygdala (LA) is believed to contribute importantly to auditory fear conditioning. This dissertation utilizes in vivo techniques to examine the molecular and physiological mechanism of LIP from thalamo-LA synapses of awake, freely-behaving rats. Prior in vitro models of synaptic plasticity have suggested that the recruitment of intracellular signaling pathways, driven by NMDAR (N-methyl-D-aspartate receptor) activation, promotes long-lasting alterations in both pre and postsynaptic sites.;This dissertation examines nitric oxide (NO) signaling and the recruitment of ERK-driven genes during thalamo-LA LTP induction. ERK refers to extracellular signal-regulated kinase. The current studies are conceptually similar to ones that were previously done using brain slices. However, there are multiple advantages for performing these experiments in vivo. One important advantage concerns confidence in the actual neuroanatomical pathway that is being stimulated in the effort to induce LTP. An obvious second advantage is that the cells are being bathed in their natural cerebrospinal fluid (CSF)-complete with the normal hormones, neuromodulators, and other important factors. A third important advantage is that the tissue is maintained at the normal body temperature. Brain slices are usually maintained at the room temperature or slightly higher. Many enzyme systems are extremely temperature dependent. Finally, of course, the in vivo approach enables one to examine behavior and neurobiology simultaneously. These are some of the main factors that motivated this in vivo approach.;Results from the experiments described here support three main conclusions. First, LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of immediate early genes (IEGs) in both LA and MGm/PIN (medial geniculate nucleus and the posterior intralaminar nucleus). Second, the induction of LTP is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 (a subtype of ionotropic glutamate receptor) and the presynaptically-localized proteins synaptophysin and synapsin at LA synapses. Third, these LTP-induced alterations were shown to be regulated by ERK and NO signaling in the LA.;Based on these data, a molecular model is proposed in which ERK-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate long-term plastic change and memory following LTP induction at thalamo-LA synapses. PKG (protein kinase G) is activated by cGMP (cyclic guanosine monophosphate). NO-driven retrograde signaling is critical for the alterations of transcription and accompanying morphological changes in LA neurons (postsynaptic) as well in MGm/PIN neurons (presynaptic).;The present results expand our knowledge and confidence beyond what was possible using brain slices. This in vivo approach to synaptic plasticity is invaluable for characterization of the mechanisms implicated in learning and memory. A few caveats about the methodology and data implication are also discussed, along with consideration of future studies that might elucidate these matters.