Pentylenetetrazol‐induced Recurrent Seizures in Rat Pups: Time Course on Spatial Learning and Long‐term Effects

Abstract

Summary:Purpose: Recurrent seizures in infants are associated with a high incidence of neurocognitive deficits. Animal models have suggested that the immature brain is less vulnerable to seizure-induced injury than is that in adult animals. We studied the effects of recurrent neonatal seizures on cognitive tasks performed when the animals were in adolescence and adulthood.Methods: Seizures were induced by intraperitoneal injection of pentylenetetrazol (PTZ) for 5 consecutive days, starting from postnatal day 10 (P10). At P35 and P60, rats were tested for spatial memory by using the Morris water maze task. In adulthood, motor performance was examined by the Rotarod test, and activity level was assessed by the open field test. Seizure threshold was examined by inhalant flurothyl. To assess presence or absence of spontaneous seizures, rats were video recorded for 4 h/day for 10 consecutive days for the detection of spontaneous seizures. Finally, brains were examined for histologic evidence of injury with cresyl violet stain and Timm staining in the supragranular zone and CA3 pyramidal cell layers of the hippocampus.Results: PTZ-treated rats showed significant spatial deficits in the Morris water maze at both P35 and P60. There were no differences in seizure threshold, motor balance, or activity level during the open field test. Spontaneous seizures were not recorded in any rat. The cresyl violet stain showed no cell loss in either the control or experimental rats. PTZ-treated rats exhibited more Timm staining in the CA3 subfield. However, the control and experimental rats showed similar Timm staining within the supragranular zone.Conclusions: Our findings indicate that recurrent PTZinduced seizures result in long-term cognitive deficits and morphologic changes in the developing brain. Furthermore, these cognitive deficits could be detected during pubescence.

Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits

“…Many children with these co-morbidities have frequent overt seizures and it is hypothesized that these seizures are partially responsible for adverse outcomes. The association between frequent generalized early life seizures and hippocampal-dependent cognition has been well studied in rodent models and support the view that epileptic discharges disrupt normal development of hippocampal networks (Chang et al, 2005; Huang et al, 1999, 2002; Liu et al, 1994). However, conclusions drawn from these models may be confounded by the effects of general brain injury due to hypoxia/ischemia and metabolic imbalance that occur at the time of the generalized seizure (McCabe et al, 2001).…”

The radial organization of neuronal primary cilia is acutely disrupted by seizure and ischemic brain injury

“…While signaling downstream of structurally-compromised neuronal primary cilia remains to be determined, pathways may have been triggered to promote aberrant neurite outgrowth or progenitor cell proliferation, which are known to occur in seizure and ischemia models (Yagita et al, 2001; Huang et al, 2002; Madsen et al, 2003; Parent et al, 2006; Sierra et al, 2015). With regard to cerebral ischemia, upregulated cytokine signaling (e.g.…”

Peroxisome proliferator-activated receptor-γ agonist inhibits the mammalian target of rapamycin signaling pathway and has a protective effect in a rat model of status epilepticus

“…This may have been the result of the epileptogenic mechanisms of PTZ and kainatediffer. PTZ-induced seizures involve blocking of the Cl-related type A γ-aminobutyric acid receptor and NMDA receptor-mediated transmission (42), while kainate is an analogue of glutamate, an excitatory amino acid neurotransmitter in the brain (43). In addition, a second peak may have occur, beyond the observation period of the present study.…”