Inhibition of Hyperactive vCA1 Rescues Social Memory in Chronic Epileptic Mice
Abstract number :
3.04
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2023
Submission ID :
980
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Anthoni Goodman, PhD – Children's Hospital of Philadelphia
Anna Bernal, N/A – CHOP; Douglas Coulter, PhD – Pediatrics – CHOP; Julia Kahn, PhD – MERK
Rationale: Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults, resultant of a range of epileptic insults to the hippocampal formation. Chronic TLE is associated with profound disruptions to cognitive, behavioral, and affective abilities which are often more disruptive to quality of life than seizures. Yet, these symptoms are resistant to available treatments, presumably yoked to permanently altered hippocampal physiology. Worse yet, comorbidities are exacerbated by the social disparities suffered by epilepsy patients. Social cognition is dependent on circuits of the ventral CA1 and their projecting outputs. Since this epilepsy-associated behavioral dysfunction is presumably based on hyperexcitable aggregate circuit properties, our overarching goal is to modify the activity of these circuits, thereby correcting social/behavioral dysfunction.
Methods: We use pilocarpine (pilo)-treated mice to verify social memory deficits in a social memory discrimination (SMD) task. This task provided two hours of homecage familiarization with a same-sex conspecific and then tested if a mouse was able to recall the familiarized mouse compared with a novel one. We next use chemogenetic tools in pilo and control mice targeting vCA1 excitatory neurons to test the effect of excitation/inhibition of these cells during social memory recall. We further target medial prefrontal cortex (mPFC) projecting vCA1 cells for chemogenetic manipulation to determine the role of output cell excitability in the social memory network.
Results: Pilo mice are unhindered in their strong preference for an olfactory social cue. Similarly, they display preference for a conspecific compared with a novel object in a social approach task, demonstrating unhindered social interest and ability to recognize social cues. Yet, even one hour after familiarization with a conspecific, pilo mice are unable to recall them in the SMD task. Excitation of a healthy vCA1 in control mice during recall recreated the social memory deficit. In pilo mice, chemogenetic inhibition of vCA1 principal cells during recall is sufficient to rescue social memory but does not modify novel object recognition showing specificity of the manipulation. Targeting output mPFC-projecting vCA1 cells for inhibition in pilo was not able to rescue social memory deficits. Targeting these same cells for moderate inhibition in control mice did not affect social memory but strong inhibition did impede performance demonstrating these cells are necessary for SMD.
Conclusions: We conclude that general vCA1 inhibition in pilo mice brings hyperexcitable cells back to a working range of excitability in which social memory recall is corrected. We further provide evidence of a tuning range of excitability, outside of which cells may detract from required circuit activity for behavior. These results demonstrate that circuit-specific modulation may be a viable therapeutic strategy to target and correct behavioral comorbidities.
Funding: NINDS grants R01NS082046, R01NS038572 to DAC
Basic Mechanisms