Heterosynaptic long‐term potentiation at interneuron–principal neuron synapses in the amygdala requires nitric oxide signalling

Abstract

Non-technical summary Long-lasting changes in efficacy of cell-cell communication (long-term potentiation; LTP) at specialized sites (synapses) between neurons in the brain are thought to underlie forms of learning and memory. These forms of LTP can occur at excitatory synapses and inhibitory synapses, thus in-or decreasing the activity of neurons. We provide evidence for a novel form of LTP at inhibitory synapses (LTP i ) on a subset of neurons in the amygdala of mice, a brain region involved in fear and anxiety. This LTP i enhances the release of the inhibitory neurotransmitter GABA at synapses between inhibitory interneurons and excitatory principal neurons (PNs) in a sub-region of the amygdala. The described LTP i is heavily dependent on the production and diffusion of the volatile gas nitric oxide (NO), produced by PNs during stages of increased activity. These findings indicate that NO-mediated long-term regulation of inhibitory transmission in the amygdala might contribute to the learning of fear.Abstract Long-lasting changes of synaptic efficacy are thought to be a prerequisite for memory formation and maintenance. In the basolateral complex of the amygdala (BLA), one of the main regions for fear and extinction learning of the brain, various forms of long-term potentiation (LTP) have been described for excitatory glutamatergic synapses. In contrast, little is known about the mechanisms of LTP at inhibitory GABAergic synapses. Here we provide evidence that (1) LTP at inhibitory GABAergic synapses (LTP i ) between inhibitory interneurons and principal neurons (PNs) can be induced by theta-burst stimulation (TBS), (2) this LTP i is prevented by AMPA-or NMDA-receptor antagonists, and (3) this LTP i is abolished by the NO synthase (NOS) inhibitor L-NAME or the NO scavenger PTIO, and thus is critically dependent on nitric oxide (NO) signalling. These findings are corroborated by immunocytochemical stainings for neuronal (n) NOS, which revealed the existence of nNOS-positive neurons and fibres in the BLA. We conclude that LTP of GABAergic synaptic transmission to PNs is induced by activation of AMPA and NMDA receptors at glutamatergic synapses and subsequent retrograde NO signalling to enhance GABAergic transmission. This form of LTP at GABAergic synapses comprises a novel form of heterosynaptic plasticity within the BLA, apt to shape conditioned fear responses.

Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation

“…1B). For example, the molecular processes associated with the regulation of neurotransmitter levels showed a 67% reduction in nNOS −/− brains, a finding consistent with previous descriptions of synaptic deficits in the nNOS −/− mice (6–14). Within the regulation of neurotransmitter level pathway, we mapped S -nitrosocysteine residues in four proteins: excitatory amino acid transporter 2, glutamate dehydrogenase, mitochondrial aspartate aminotransferase, and glutamine synthetase (Fig.…”

NO regulates the strength of synaptic inputs onto hippocampal CA1 neurons via NO-GC1/cGMP signalling

“…In sum, the data speak in favour of a direct role of NO-GC1 in the presynaptic GABA release, which does not exclude additional sites of NO-GC1 action. Our findings of NO-GC1 enhancing GABA release are supported by a vast body of evidence from others showing the involvement of NO signalling in enhancing neurotransmitter release from GABAergic synapses in hippocampus [32], amygdala [12], paraventricular nucleus of hypothalamus [14,15], ventral tegmental area [20,21] and supraoptic nucleus [25]. Activation of nNOS in response to rises in intracellular Ca 2+ during electrical stimulation generates NO, which then travels retrogradely to stimulate NO-GC1 in neighbouring presynaptic GABAergic terminals.…”

Heterosynaptic Regulation of External Globus Pallidus Inputs to the Subthalamic Nucleus by the Motor Cortex

“…Nugent et al, 2007; Lange et al, 2012). Because STN neurons express NOS (Nisbet et al, 1994) and GPe neurons express soluble GC (Pifarre et al, 2007) the involvement of NO signaling in hLTP of GPe-STN transmission was tested.…”