Authors :
Presenting Author: Cynthia Daut, BA – Rutgers Robert Wood Johnson Medical School
Fabio Tescarollo, PhD – Rutgers University
Spencer Chen, PhD – Rutgers University
Hai Sun, MD, PhD – Rutgers University
Rationale:
The striatum, a portion of the basal ganglia that coordinates motor learning, is implicated in the pathogenesis of hippocampus-originated seizures in mesial temporal lobe epilepsy (mTLE). mTLE is characterized by the recurrence of spontaneous seizures that can affect additional areas through the spreading of hypersynchronous activity, with known comorbidities of motor learning and memory decline. Using an optogenetic kindling mouse model (OpK) of mTLE targeting CA1 hippocampal neurons, we previously showed that repetitive activation of these neurons over time results in progressively increased seizure severity and duration. We aimed to examine whether excitatory and inhibitory synaptic marker levels are associated with cognitive deficits secondary to progressive seizure intensification.
Methods:
We used an OpK model of mTLE (n=14) to induce progressively severe and generalized seizures. Intra-hippocampal kainic acid-injected mice (KA) (n=10) served as a model for chronic mTLE, with naïve mice (n=12) as controls. Morris water maze (WMT) and novel object recognition (NORT) tests were conducted to investigate changes in spatial learning and memory during kindling progression.
Results:
Repeated seizure exposure resulted in increased GABAa expression with accompanying deficits in hippocampal and dorsolateral striatum-dependent spatial memory performance. KA and OpK mice showed respective 723% (p< 0.0001) and 417% (p=0.0001) increases in GABAa expression compared to naïve mice in the hippocampus, with KA mice showing a greater increase in hippocampal GABAa compared to OpK mice (p=0.0151). KA and OpK mice showed respective 257% (p< 0.0001) and 160% (p=0.0002) increases in striatal GABAa expression. No statistically significant changes were observed in vGlut1 for KA or OpK. Morris water maze (WMT) and novel object recognition (NORT) tests were conducted to investigate alterations in spatial learning and memory. OpK mice showed decreased WMT target crossings compared to pre-kindling trials (p=0.001, paired t-test). Compared to pre-KA injection trials, KA mice trended toward fewer crossings (p=0.0564, paired t-test). Memory deficits from NORT were inconclusive.
Conclusions:
Marked changes in GABAa expression without clear vGlut1 changes indicate that primary alterations in kindling and chronic epilepsy lie in the inhibitory synapses, suggesting increased sensitivity to GABAergic inhibition in striatal projection neurons. This is likely a curbing response to the overwhelming excitatory drive of seizure activity. In the chronic epilepsy model, which causes hippocampal sclerosis, increased sensitivity may be further driven by a loss of GABAergic neurons. Between active seizures, this increased inhibition sensitivity may produce a lower basal activity level, thus impairing normal functions of affected brain regions. Reduced memory-associated behavior performance likely reflects depressed neural processing in the hippocampus and striatum as a result of acute GABAa synaptic changes, rather than chronic pathology.
Funding:
No external funding for this project.