GluN1/3A NMDA receptor–dependent synaptic remodeling in mPFC SST-INs reveals a neurocircuit mechanism of PTSD
Presentation Type
Poster Presentation
Category
STEM (science, technology, engineering, mathematics)
Abstract/Artist Statement
Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that affects millions worldwide and has poor therapeutic outcomes. The locus of encoded fear memories is unknown, which has delayed therapeutic intervention. It is known that appropriate responses to threats require disinhibition of medial prefrontal cortex (mPFC) glutamatergic outputs. However, inappropriate threat responses may be caused by disruption of the inhibitory/excitatory balance that regulates glutamatergic outputs. Dendritic spines are points of contact between neurons to send electrical or chemical signals. Changes in shape and number of dendritic spines contribute to memory storage. Recently, a subset of interneurons expressed in the mPFC, GABAergic somatostatin interneurons (SST-INs), have been shown to encode the association between the cues that predict threats. In a mouse model of PTSD, we found an increase in glutamatergic spines on SST-INs in the mPFC, suggesting that these excitatory inputs could be a locus of fear memory storage. Importantly, when naive mice have a constitutive deletion of N-methyl-D-aspartate (NMDA) receptor subunit GluN3A (3AKO), the spine morphology resembles a fear-conditioned mouse in mPFC SST-INs. Moreover, 3AKO mice exhibit increased fear responses at 24 hours. These results suggest that GluN3A plays a role in fear learning and memory consolidation, potentially through regulation of dendritic spines on mPFC SST cells. In this study, we utilize male and female wildtype (WT) and transgenic mice to understand how changes in synaptic plasticity contribute to changes in neurocircuitry within the mPFC. Electrophysiological experiments were done by measuring the baseline changes in synaptic transmission in 3AKO and WT mice in SST-INs and projection neurons (PNs). Through whole-cell patch clamp, we show that PNs are more excitable at baseline in 3AKO than their WT counterparts, however SST-INs are not. These data suggest that SST-INs do not directly synapse onto PNs but are rather disinhibiting other GABAergic interneurons.
Mentor Name
Emma Janae Nicolaisen
GluN1/3A NMDA receptor–dependent synaptic remodeling in mPFC SST-INs reveals a neurocircuit mechanism of PTSD
UC North Ballroom
Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that affects millions worldwide and has poor therapeutic outcomes. The locus of encoded fear memories is unknown, which has delayed therapeutic intervention. It is known that appropriate responses to threats require disinhibition of medial prefrontal cortex (mPFC) glutamatergic outputs. However, inappropriate threat responses may be caused by disruption of the inhibitory/excitatory balance that regulates glutamatergic outputs. Dendritic spines are points of contact between neurons to send electrical or chemical signals. Changes in shape and number of dendritic spines contribute to memory storage. Recently, a subset of interneurons expressed in the mPFC, GABAergic somatostatin interneurons (SST-INs), have been shown to encode the association between the cues that predict threats. In a mouse model of PTSD, we found an increase in glutamatergic spines on SST-INs in the mPFC, suggesting that these excitatory inputs could be a locus of fear memory storage. Importantly, when naive mice have a constitutive deletion of N-methyl-D-aspartate (NMDA) receptor subunit GluN3A (3AKO), the spine morphology resembles a fear-conditioned mouse in mPFC SST-INs. Moreover, 3AKO mice exhibit increased fear responses at 24 hours. These results suggest that GluN3A plays a role in fear learning and memory consolidation, potentially through regulation of dendritic spines on mPFC SST cells. In this study, we utilize male and female wildtype (WT) and transgenic mice to understand how changes in synaptic plasticity contribute to changes in neurocircuitry within the mPFC. Electrophysiological experiments were done by measuring the baseline changes in synaptic transmission in 3AKO and WT mice in SST-INs and projection neurons (PNs). Through whole-cell patch clamp, we show that PNs are more excitable at baseline in 3AKO than their WT counterparts, however SST-INs are not. These data suggest that SST-INs do not directly synapse onto PNs but are rather disinhibiting other GABAergic interneurons.