Abstracts

Rationale: People with epilepsy have a significantly higher lifetime risk of developing psychiatric disorders including depression and anxiety. Despite the high incidence rate and debilitating effects of comorbid anxiety, our understanding of the neurobiology underlying the onset of comorbid anxiety is nascent; however, research implicates the amygdala in the network communication of anxiety and fear. Previous work has examined the impact of chronic epilepsy on vulnerable neuronal populations in the amygdala, including somatostatin and parvalbumin (PV) interneurons (INs). Hippocampal PV INs are known to be vulnerable to chronic epilepsy induced cell loss (CEICL), and preliminary evidence shows this occurs in the basolateral amygdala (BLA) as well. BLA PV INs play a critical role in both the generation of local network oscillations and control over the local network state governing behavioral expression of anxiety and fear¹. Given the important role of BLA PV INs in regulating network communication of anxiety and their vulnerability to CEICL, we hypothesize that CEICL of BLA PV INs results in pathological changes which prevent the network from switching between the network communication of safety and anxiety², leading to the development of comorbid anxiety in chronically epileptic mice.

Methods: A chemconvulsant temporal lobe epilepsy model using ventral intrahippocampal kainic acid (vIHKA) injection displays affective phenotypes associated with depression and anxiety in addition to pathology comparable to the dorsal IHKA model³. Further, BLA PV-specific effects were examined with PV-cre/lox-Diphtheria toxin A (DTA), and PV-cre/hM4Di DREADD systems. Using whole-cell patch clamp electrophysiology, in vivo, and ex vivo local field potential (LFP) recordings, we determined the effects of chronic epilepsy on PV INs within the BLA of vIHKA and control mice. Cell-intrinsic and synaptic properties of BLA PV INs were analyzed from single cell patch recordings, while network communication properties were analyzed from in vivo and ex vivo BLA LFP recordings.

Results: Both vIHKA and DTA-PV mice exhibit a significant loss of PV-immunoreactive neurons within the BLA. The remaining PV INs within the BLA of vIHKA treated mice exhibit reduced intrinsic excitability and less frequent, larger amplitude synaptic inputs. DTA-injected mice exhibit an inability to switch between network states signaling the network communication of fear and anxiety. The loss of PV INs either by CEICL or genetically targeted DTA ablation may underlie the corruption of network communication of anxiety in comorbid anxiety and epilepsy.

Conclusions: Here, our data show chronically epileptic mice and DTA-injected PV-cre mice exhibit a significant loss of BLA PV INs, and impaired network communication of anxiety compared to control mice. Corrupted network oscillations stemming from a loss of BLA PV INs may underlie the inappropriate network communication of safety and contribute to comorbid anxiety and epilepsy.

1. Stujenske et al. Neuron 83, 919–933 (2014).
2. Davis et al. Nat Neurosci 20, 1624–1633 (2017).
3. Zeidler, et al. eNeuro 5, 0158–18 (2018).

Funding: Please list any funding that was received in support of this abstract.: This work was supported by R01NS105628, and R01NS102937.