Altered behavior in experimental cortical dysplasia

Abstract

Summary Purpose Developmental delay and cognitive impairment are common comorbidities in people with epilepsy associated with malformations of cortical development (MCDs). We studied cognition and behavior in an animal model of diffuse cortical dysplasia (CD), in utero irradiation, using a battery of behavioral tests for neuromuscular and cognitive function. Methods Fetal rats were exposed to 2.25 Gy external radiation on embryonic day 17 (E17). At 1 month of age they were tested using an open field task, a grip strength task, a grid walk task, inhibitory avoidance, an object recognition task, and the Morris water maze task. Key Findings Rats with CD showed reduced nonlocomotor activity in the open field task and impaired motor coordination for grid walking but normal grip strength. They showed a reduced tendency to recognize novel objects and reduced retention in an inhibitory avoidance task. Water maze testing showed that learning and memory were impaired in irradiated rats for both cue discrimination and spatially oriented tasks. These results demonstrate significant deficits in cortex-and hippocampus-dependent cognitive functions associated with the diffuse abnormalities of cortical and hippocampal development that have been documented in this model. Significance This study documents multimodal cognitive deficits associated with CD and can serve as the foundation for future investigations into the mechanisms of and possible therapeutic interventions for this problem.

Impaired hippocampal memory function and synaptic plasticity in experimental cortical dysplasia

“…This study utilized the irradiated rat model of CD and found an impairment of spatial recognition memory using a place recognition task, which is hippocampal CA1‐dependent (Brun et al., 2002). Irradiated rats demonstrate impaired nonspatial object recognition memory revealed by an object recognition task (Zhou et al., 2011), which is neocortex dependent (Brown & Aggleton, 2001). Irradiated rats also show impaired spatial navigation memory in the Morris water maze task (Zhou et al., 2011), which is hippocampus (subregions CA1, CA3, and dentate gyrus) dependent (Morris et al., 1982; Clark et al., 2007).…”

“…Hippocampal pyramidal neurons of irradiated rats also exhibit higher excitability and lower synaptic inhibition than controls (Smith et al., 1999). The widespread loss, dysfunction, and disorganization of neuronal populations in the irradiated rat brain would be likely to cause co‐morbidities such as impaired cognitive functions, and a recent study has confirmed significantly impaired nonspatial recognition memory and spatial navigation memory in these animals (Zhou et al., 2011). But the mechanisms responsible for impaired memory function in CD are poorly understood.…”

Quetiapine attenuates cognitive impairment and decreases seizure susceptibility possibly through promoting myelin development in a rat model of malformations of cortical development

“…One of the most common and serious co-morbidities in patients with MCD is cognitive impairment. Irradiated rats showed a reduced tendency to recognize novel objects in addition to impaired spatial learning and memory (Lucas et al, 2011;Zhou et al, 2011). Therefore, there is a need for research investigating possible pharmacological interventions for MCDassociated cognitive impairment.…”

“…Objects were high enough to ensure that the rats could not climb over them. The task consisted of an acquisition phase and a retention phase as previously described (Zhou et al, 2011). During the sample phase, two identical objects (Object 1 and Object 2) were placed at either end of the box.…”

Genetic animal models of malformations of cortical development and epilepsy

“…Irradiated rats also show increased susceptibility to seizures in response to pilocarpine (Setkowicz et al, 2003). Irradiated rats show learning and memory impairment relative to both hippocampal and neocortical dysfunction (Zhou et al, 2011) and long-term potentiation is impaired in the CA1 region of the hippocampus in irradiated rats (Zhou and Roper, 2012). This means that this model recapitulates one of the most common and debilitating co-morbidities seen in humans with intractable epilepsy.…”