GABAb Receptor Mediates Opposing Adaptations of GABA Release From Two Types of Prefrontal Interneurons After Observational Fear

Abstract

The observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences.

Overexpression of Channelrhodopsin 2 interferes with the GABAb receptor-mediated depression of GABA release from the somatostatin-containing interneurons of the prefrontal cortex

“…A comparison was made between slices expressing "high" and "low" levels of ChR2-YFP, which were obtained from animals transduced with 1 x 10 8 To examine the role of GABAb receptor in the synaptic plasticity, IPSCs were recorded first in ACSF without drugs and then, after 10 min perfusion with 10 µM of CGP52432, a GABAb receptor blocker. The IPSC data from the low virus slices are a part of an earlier publication (6), but are included here to allow for the comparison between the high and low virus conditions. The IPSC amplitudes decreased along the train in both the low and the high virus groups (low virus: F(4,10) = 121, p<0.0001; high virus: F(4, 9) = 82, p<0.0001), but the decreases in the low virus group were greater ("train" * "level of virus" interaction, F (4,19) = 17.4, p<0.0001) (Fig.1E).…”

“…Electrophysiology. Slice preparation and recordings were performed as described in (6). Coronal dmPFC slices, 300 µm thickness, were prepared from p60-75 mice using DSK Microslicer (Ted Pella, Redding, CA) and ice cold cutting solution contained (in mM) 110 Choline Cl, 2.5 KCl, 1.2 NaH 2 PO 4 , 2.5 NaHCO 3 , 20 glucose, 0.5 CaCl 2 , and 5 MgSO 4 , bubbled with a 95% O 2 /5% CO 2 .…”

“…In the insular and somatosensory cortex of the rat brain, such depression is particularly pronounced when the interval between stimuli is around 200 ms (14,15). Recently, we have shown that in brain slices from the mouse dorsomedial prefrontal cortex (dmPFC), GABA release from the somatostatin-positive GABAergic neurons (SOM-INs) expressing ChR2 undergoes strong presynaptic GABAb receptor-mediated depression during their stimulation with the 5Hz frequency train of blue light pulses (6). Here, we compared the GABA depression between two groups of slices prepared from the brains transduced with two different amounts of AAV expressing ChR2, and found that the higher viral quantities diminished the GABAb receptor-mediated depression of GABA release from SOM-IN of dmPFC.…”

Neural Basis of Observational Fear Learning: A Potential Model of Affective Empathy

“…Because PV neurons generally target the somas of pyramidal neurons, whereas dendrite-targeting SST neurons exert distal inhibition to control incoming inputs to pyramidal neurons (Gentet et al, 2012;Tremblay et al, 2016), these findings suggest that SST neuron-specific inhibitory mechanisms in the ACC microcircuit are responsible for vicarious transmission of social fear. Following observational fear learning, ex vivo slice recording showed that the inhibitory drive was shifted from the soma to the distal dendrites of pyramidal neurons in the ACC (Liu et al, 2017). It is yet to be determined what physiological function this plasticity has.…”

Distinct Synchronous Network Activity During the Second Postnatal Week of Medial Entorhinal Cortex Development

“…Notably, the distribution and action of GABA-B receptors may not be homogenous throughout the network. Research in the prefrontal cortex has shown that presynaptic GABA-B activation causes short-term depression of inhibitory inputs, and that inputs from somatostatin (SST)-expressing interneurons (SST-INs) are more strongly affected than those of parvalbumin (PV)-expressing interneurons (Liu et al, 2017). Hub cells that strongly influence SSNA tend to be SST-INs (Mòdol et al, 2017).…”