Colmers Phillip L W, Antonoudiou Pantelis, Basu Trina, Coleman Emanuel M, He Yingchu, Scapa Garrett, Fuller Patrick, Maguire Jamie
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
Department of Neurological Surgery, UC Davis Health, Sacramento, California 95817.
eNeuro. 2025 Jan 17;12(1). doi: 10.1523/ENEURO.0482-23.2024. Print 2025 Jan.
Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid model of TLE in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of the remaining PV interneurons in the BLA of chronically epileptic mice. Furthermore, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether the loss of PV interneurons contributes to these altered network and behavioral states, we partially ablated PV interneurons in the BLA by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, such as increasing avoidance behaviors and impairing fear learning. These data suggest that compromised inhibition in the BLA in chronically epileptic mice may contribute to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy.
精神疾病，包括焦虑症和抑郁症，在癫痫患者中高度共病。然而，介导共同病理生理学的机制目前尚不清楚。有大量证据表明基底外侧杏仁核（BLA）参与焦虑和恐惧的网络通信，这一过程已被证明涉及小白蛋白阳性（PV）中间神经元。在慢性癫痫小鼠的海马体以及颞叶癫痫（TLE）患者的死后人体组织中，PV中间神经元的丧失已有充分描述。我们假设BLA中PV中间神经元的丧失可能导致癫痫患者共病情绪障碍。为了验证这一假设，我们在小鼠中采用了腹侧海马内注射 kainic 酸的TLE模型，该模型表现出与慢性癫痫相关的严重行为缺陷。我们证明了慢性癫痫小鼠BLA中PV中间神经元的丧失以及剩余PV中间神经元的功能障碍。此外，我们还证明了慢性癫痫小鼠中主要神经元功能的改变以及BLA网络与行为状态协调的受损。为了确定PV中间神经元的丧失是否导致这些网络和行为状态的改变，我们通过立体定向将AAV-Flex-DTA注射到PV-Cre小鼠的BLA中，部分消融了BLA中的PV中间神经元。BLA中PV中间神经元的丧失足以改变行为状态，如增加回避行为和损害恐惧学习。这些数据表明，慢性癫痫小鼠BLA中抑制功能受损可能导致行为缺陷，提示了一种导致共病焦虑和癫痫的新机制。
