Enriched environment ameliorates chronic temporal lobe epilepsy‐induced behavioral hyperexcitability and restores synaptic plasticity in CA3–CA1 synapses in male Wistar rats

Abstract

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies.Pharmacoresistance and comorbidities pose significant challenges to its treatment necessitating the development of non-pharmacological approaches. In an earlier study, exposure to enriched environment (EE) reduced seizure frequency and duration and ameliorated chronic epilepsy-induced depression in rats. However, the cellular basis of beneficial effects of EE remains unknown. Accordingly, in the current study, we evaluated the effects of EE in chronic epilepsy-induced changes in behavioral hyperexcitability, synaptic transmission, synaptophysin (SYN), and calbindin (CB) expression, hippocampal subfield volumes and cell density in male Wistar rats.Epilepsy was induced by lithium-pilocarpine-induced status epilepticus. Chronic epilepsy resulted in behavioral hyperexcitability, decreased basal synaptic transmission, increased paired-pulse facilitation ratio, decreased hippocampal subfields volumes. Moreover, epileptic rats showed decreased synaptophysin and CB expression in the hippocampus. Six weeks post-SE, epileptic rats were exposed to EE for 2 weeks, 6 hr/ day. EE significantly reduced the behavioral hyperexcitability and restored basal synaptic transmission correlating with increased expression of SYN and CB. Our results reaffirm the beneficial effects of EE on behavior in chronic epilepsy and establishes some of the putative cellular mechanisms. Since drug resistance and comorbidities are a major concern in TLE, we propose EE as a potent non-pharmacological treatment modality to mitigate these changes in chronic epilepsy.

Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

“…Another way to study changes in synaptic density during epileptogenesis is to quantify synaptic proteins such as SV2A, synaptophysin or synaptotagmin (see Figure 3). Indeed, these proteins are mostly decreased in preclinical models of epilepsy, which could be reversed by pharmacological treatments or by exposure to an enriched environment (van Vliet et al, 2009;Hanaya et al, 2012;Salaka et al, 2021), confirming the aforementioned utility of synaptic IHC as biomarker of epilepsy. On the other hand, reports of increases in the expression of the same markers (Contreras-García et al, 2018;Wang et al, 2018), highlight the possible presence of compensatory mechanisms including, for example, an increase in GABAergic neurotransmission (Ohno et al, 2012).…”

Repeated finasteride administration promotes synaptic plasticity and produces antidepressant‐ and anxiolytic‐like effects in female rats

“…The hippocampal slices were then transferred to a slice incubating chamber (BSK4‐Quad; AutoMate Scientific Inc., CA, USA, ) filled with carbogenated aCSF. These slices were incubated in slice keeper for 2 h at room temperature (Salaka et al., 2021, 2022; Subhadeep et al., 2021).…”

Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

“…For instance, an enriched environment was shown to reduce epilepsy-induced behavioral hyperexcitability and depression in the lithium-pilocarpine model. 189,190 Moreover, an enriched environment reduced seizure episodes and seizure duration in epileptic rats but neither ameliorated epilepsy-induced spatial learning and memory deficits nor restored cell density in the hippocampus. 190 In the amygdala kindling model, early-in-life exposure to environmental enrichment significantly retarded kindling acquisition, reduced kindling-associated anxiety, and reduced aberrant mossy fiber sprouting.…”

“…Furthermore, environmental enrichment may affect the behavior of rodents before, during, and after the induction of epilepsy. For instance, an enriched environment was shown to reduce epilepsy‐induced behavioral hyperexcitability and depression in the lithium–pilocarpine model 189,190 . Moreover, an enriched environment reduced seizure episodes and seizure duration in epileptic rats but neither ameliorated epilepsy‐induced spatial learning and memory deficits nor restored cell density in the hippocampus 190 .…”