A Single Episode of Seizures Induced by Pentylenetetrazole is Followed by a Cognitive Decline

INTRODUCTION

According to different studies, between 5% and 10% of people suffer a single isolated seizure at some time in their life. However, little is known about effects of a single seizure on the cognitive function, and clinical investigations of this issue are not easy to perform. The aim of our study was to follow the time course of delayed effects of generalized clonic-tonic convulsions on learning and memory functions in rats.

MEMORY TESTS

We have injected rats with a submaximal dose of a hemoconvulsant pentylenetetrazole (PTZ, 70 mg/kg) and measured their memory performance during three subsequent months using novel object recognition test and social recognition test (Fig.1). In both tests, PTZ-induced generalized tonic-clonic seizures were accompanied by a slowly developing decline in short-term non-spatial memory.

Fig.1. Performance of short-term memory in novel object recognition test (A) and social recognition test (B) after PTZ-induced seizures in rats.

IMMUNOHISTOCHEMICAL STUDY

The temporal profile of progression of memory impairments along with the absence of profound neuronal damage (as assessed by vanadium acidic fuchsine stain) after PTZ-induced convulsions allowed us to suggest the involvement of aberrant seizure-induced adult neurogenesis in the pathogenesis of observed memory dysfunction. To verify this hypothesis, we injected the rats with S-phase marker 5-bromo-2-deoxyuridine  (BrdU) and counted the number of labeled cells in the dentate gyrus (DG) at different time points after the seizures (Fig. 2). We have found that simultaneously with development of memory impairments, an elimination of excessive young cells occurs in the germinative area of the hippocampus. The possible mechanism of aberrant maturation of the newly generated cells in the absence of their visible structural abnormality can be launched by

the neuroinflammatory alteration of the local microenvironment within the neurogenic niche. To check this supposition we stained rat brain slices for glial markers Iba-1 (microglial cells) and GFAP (astrocytes) and analyzed their expression at different time points after the seizures (Fig. 3). On the next day after the seizures an activation of microglial cells occurred in the DG.Two weeks later, no signs of microglial activation were present; moreover, astrocytic glia was also not increased in number and size as assessed by GFAP immunostaining suggesting no chronic neuroinflammation after single PTZ-induced convulsion.

Fig.3. Expression at different time points after the seizures

CONCLUSIONS

Single episode of generalized tonic-clonic seizures induced by PTZ led to slowly developing memory impairments in rats, accompanied by elimination of excessive newly generated young cells and transient activation of microglial cells in this neurogenic niche. The study was partially supported by RFH grant # 13-36-01277 and RFBR grant # 14-04-3152.