Disinhibition-assisted LTP in the prefrontal-amygdala pathway via suppression of somatostatin-expressing interneurons

Abstract

Natural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help 10 investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like 11 correlated neuronal firing and oscillations but also in behaviors. High and low-frequency stimulation at presynaptic 12 sites has been used widely to induce long-term potentiation (LTP) and depression (LTD), respectively. This approach 13 is effective in many brain areas, but not in the basolateral amygdala (BLA), because the robust local GABAergic tone 14 inside the BLA restricts synaptic plasticity. Here, we identified the subclass of GABAergic neurons that gate LTP in 15 the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Chemogenetic suppression of somatostatin-16 positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent, but the 17 suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs 18 with Arch also enabled LTP of the dmPFC-BLA synapses both ex vivo and in vivo. These findings reveal that Sst-INs 19 but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA. 20 21 24 25 26Circuit interrogation using the optogenetics and chemogenetics has become a standard approach 27 for testing the causal role of specific neuronal populations and synapses in brain activities and 28 animal behaviors. The techniques employ depolarizing or hyperpolarizing neuronal compartments, 29 like the soma, dendrites, and synaptic terminals, to trigger or suppress the action potentials and 30 release of neurotransmitter (1, 2). Meanwhile, the natural neuronal adaptations driven by 31 experience and learning, or observed during development or in disease, involve brain alterations, 32 not only in the neuronal activity but also in the synaptic efficacy. For example, the auditory fear 33 conditioning, a model of adaptive defensive behavior, strengthens the auditory inputs to the lateral 34 amygdala (3), whereas the fear extinction training depresses the prefrontal-amygdala synapses and 35 strengthens the reciprocal amygdala-prefrontal synapses (4, 5). Modeling and quantitative analyses 36 of such naturally occurring brain adaptations require methods for selective manipulation of the 37 synaptic strength both ex vivo and in vivo. 38 By applying high-or low-frequency presynaptic stimulation, synapses, in many cases, can 39 be potentiated or depressed, respectively (6). This simple technique has been employed in 40 optogenetics for manipulating synaptic strength ex vivo and in vivo and proved successful in 41 several cases. LTP was obtained in the recurrent synapses in hippocampal area CA3 by applying 42 20 Hz stimulation (7) and in the cortico-striatal synapses by applying the theta-burst stimulation 43 (8). LTD was obtained in the inputs to the nucleus accumbens from the infralimbic cortex and 44 basolateral amygdala by applying the low-freq...

Hyperexcitability and Loss of Feedforward Inhibition Contribute to Aberrant Plasticity in theFmr1KO Amygdala

“…Future studies should address the idiosyncrasies of how loss of Fmr1 affects distinct neural circuits across the brain and their corresponding behaviors. Converging evidence from our group and others implicates LA Sst + INs in FFI gating of LTP ( Smith et al, 2000 ; Bissière et al, 2003 ; Unal et al, 2014 ; Wolff et al, 2014 ; Ito et al, 2019 ; Guthman et al, 2020 ). However, it remains to be shown if specific alterations in Sst + IN function underlie the facilitated LTP seen in Frm1 KO LA.…”

“…The local circuit INs play an important role regulating the synaptic plasticity underlying this in vivo learning process ( Bissière et al, 2003 ; Wolff et al, 2014 ). Our group and others have shown this inhibitory control is exerted via a feedforward circuit motif from somatostatin-expressing (Sst) INs which modulates long-term potentiation (LTP) at cortical and thalamic afferent synapses onto BLA PNs ( Smith et al, 2000 ; Bissière et al, 2003 ; Tully et al, 2007 ; Unal et al, 2014 ; Wolff et al, 2014 ; Bazelot et al, 2015 ; Ito et al, 2019 ; Guthman et al, 2020 ). Thus, feedforward inhibition (FFI)-gated LTP is an underlying circuit mechanism for the acquisition of threat conditioning.…”

Hyperexcitability and loss of feedforward inhibition in theFmr1KO lateral amygdala

“…The local circuit INs play an important role regulating the synaptic plasticity underlying this in vivo learning process (Bissière et al , 2003; Wolff et al , 2014). Our group and others have shown this inhibitory control is exerted via a feedforward circuit motif from somatostatin-expressing (Sst) INs which modulates long-term potentiation (LTP) at cortical and thalamic afferent synapses onto BLA PNs (Smith et al , 2000; Bissière et al , 2003; Tully et al , 2007; Wolff et al , 2014; Unal et al , 2014; Bazelot et al , 2015; Ito et al , 2019; Guthman et al , 2020). Thus, feedforward inhibition-gated LTP is an underlying circuit mechanism for the acquisition of threat conditioning.…”