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Published on: June 29, 2022
Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model
Wenjie Zou1, Zhipeng Guo1, Longge Suo1
1Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Abstract:
Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures which in some conditions can develop into secondarily generalized tonic-clonic seizures by the propagation of epileptic activities in the temporal lobe to other brain areas. The nucleus accumbens (NAc) has been suggested as a treatment target for TLE as accumulating evidence indicates that the NAc, especially its shell, participates in the process of epileptic seizures of patients and animal models with TLE. The majority of neurons in the NAc are GABAergic medium spiny neurons (MSNs) expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). However, the direct evidence of the NAc shell participating in the propagation of TLE seizures is missing, and its cell type-specific modulatory roles in TLE seizures are unknown. In this study, we microinjected kainic acid into basolateral amygdala (BLA) to make a mouse model of TLE with initial focal seizures and secondarily generalized seizures (SGSs). We found that TLE seizures caused robust c-fos expression in the NAc shell and increased neuronal excitability of D1R-expressing MSN (D1R-MSN) and D2R-expressing MSN (D2R-MSN). Pharmacological inhibition of the NAc shell alleviated TLE seizures by reducing the number of SGSs and seizure stages. Cell-type-specific chemogenetic inhibition of either D1R-MSN or D2R-MSN showed similar effects with pharmacological inhibition of the NAc shell. Both pharmacological and cell-type-specific chemogenetic inhibition of the NAc shell did not alter the onset time of focal seizures. Collectively, these findings indicate that the NAc shell and its D1R-MSN or D2R-MSN mainly participate in the propagation and generalization of the TLE seizures.
Insights
The nucleus accumbens shell, including its D1R-MSN and D2R-MSN neurons, plays a key role in temporal lobe epilepsy (TLE) seizure generalization. Inhibiting these neurons reduces seizure severity, offering potential therapeutic targets for TLE.
Area of Science:
- Neuroscience
- Epilepsy Research
- Molecular Psychiatry
Background:
- Temporal lobe epilepsy (TLE) is the most common epilepsy type, characterized by focal seizures that can generalize.
- The nucleus accumbens (NAc), particularly its shell, is implicated in TLE, but its specific role and cell-type involvement remain unclear.
- Medium spiny neurons (MSNs) expressing dopamine receptor D1 (D1R) or D2 (D2R) constitute the majority of NAc neurons.
Purpose of the Study:
- To investigate the direct evidence of the NAc shell's participation in TLE seizure propagation.
- To elucidate the cell type-specific modulatory roles of NAc neurons in TLE seizures.
- To evaluate the therapeutic potential of targeting the NAc shell for TLE treatment.
Main Methods:
- A mouse model of TLE was established by microinjecting kainic acid into the basolateral amygdala (BLA).
- c-fos expression and neuronal excitability in the NAc shell were assessed in TLE mice.
- Pharmacological and chemogenetic inhibition strategies were employed to target the NAc shell and its specific MSN subtypes (D1R-MSN, D2R-MSN).
Main Results:
- TLE seizures induced significant c-fos expression and increased neuronal excitability in the NAc shell.
- Inhibition of the NAc shell, or specifically D1R-MSNs or D2R-MSNs, reduced the severity and generalization of TLE seizures.
- These interventions did not affect the onset of initial focal seizures, suggesting a role in propagation.
Conclusions:
- The NAc shell, comprising D1R-MSNs and D2R-MSNs, is critically involved in the propagation and generalization of TLE seizures.
- Targeting the NAc shell offers a promising therapeutic strategy for mitigating TLE seizure severity.
- This study provides direct evidence for the NAc shell's role in TLE pathophysiology.
