Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy

Abstract

Learning and memory dysfunction is the most common neuropsychological effect of mesial temporal lobe epilepsy, and because the underlying neurobiology is poorly understood, there are no pharmacological strategies to help restore memory function in these patients. We have demonstrated impairments in the acquisition of an allocentric spatial task, in patients with unilateral hippocampal sclerosis. We also show that patients have accelerated forgetting of the learned spatial task and that this is associated with damage to the non-dominant hippocampal formation. We go on to show a very similar pattern of chronic allocentric learning and accelerated forgetting in a status epilepticus model of mesial temporal lobe epilepsy in rats, which is associated with reduced and abnormal hippocampal neurogenesis. Finally, we show that reversal of the neurogenic deficit using fluoxetine is associated with reversal of the learning deficit but not the accelerated forgetting, pointing to a possible dissociation in the underlying mechanisms, as well as a potential therapeutic strategy for improving hippocampal-dependant learning in patients with mesial temporal lobe epilepsy.

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

“…We describe for the first time that a reduced rate of learning and an accelerated forgetting are two specific features of rats prone to develop epilepsy, and these deficits anticipate the onset of spontaneous seizures. Notably, impaired spatial learning and accelerated forgetting were also described in temporal lobe epilepsy (TLE) patients exposed to a virtual MWM task (Barkas et al, 2012) and cognitive deficits were documented in children and adult before the first recognized seizures or at…”

Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

“…These specific cognitive features were observed only in rats prone to develop epilepsy and persisted in the chronic epilepsy phase [54]. Notably, the same deficits were described in patients with temporal lobe epilepsy who were exposed to a virtual spatial learning task [62]. Since cognitive deficits have been described in human epilepsy before the onset, or at early stages, of the disease [57][58][59] they could represent sensitive and specific biomarkers of epileptogenesis.…”

“…(c) Layout of pool, platform position and objects located on the walls surrounding the pool in the context of a virtual navigation maze designed for testing spatial memory in humans [57]. The dot in the circle represents the person's view from the centre of the pool toward the north-west corner of the virtual water maze environment [62]. A decay in the rate of learning and accelerated forgetting are common cognitive deficits of animals developing epilepsy [41] and human temporal lobe epilepsy [62], and in animal models these neurobehavioral features anticipate the onset of spontaneous seizures [41].…”

“…The dot in the circle represents the person's view from the centre of the pool toward the north-west corner of the virtual water maze environment [62]. A decay in the rate of learning and accelerated forgetting are common cognitive deficits of animals developing epilepsy [41] and human temporal lobe epilepsy [62], and in animal models these neurobehavioral features anticipate the onset of spontaneous seizures [41]. Animal studies suggest that cognitive deficits and increased excitability resulting in seizures may be reflected by an increased activation of sub-populations of GFAPpositive astrocytes which express S100β (see text for details) [93].…”

Study of the effect of antidepressant drugs and donepezil on aluminum-induced memory impairment and biochemical alterations in rats

“…Other researchers have reported improved reference memory (food finding time in the maze) after chronic treatment with 5 mg/kg fluoxetine (Nowakowska et al 2000). In a status epilepticus model of mesial temporal lobe epilepsy in rats, fluoxetine treatment resulted in reversal of the learning deficit (though not the accelerated forgetting) (Barkas et al 2012). Studies have also shown improvement in memory performance in rodents by tricyclic antidepressant drugs.…”