Exposure to bacterial lipopolysaccharidein early life affects the expression of ionotropic glutamate receptor genes and is accompanied by disturbances in long-term potentiation and cognitive functions in young rats.

Infections in childhood play an essential role in the pathogenesis of cognitive and psycho-emotional disorders. One of the possible mechanisms of these impairments is changes in the functional properties of NMDA and AMPA glutamate receptors in the brain. We suggest that bacterial infections during the early life period, which is critical for excitatory synapse maturation, can affect the subunit composition of NMDA and AMPA receptors. In the present study, we investigated the effect of repetitive lipopolysaccharide (LPS) intraperitoneal (i.p.) administration (25 µg/kg/day on P14, 16, and 18), mimicking an infectious disease, on the expression of subunits of NMDA and AMPA receptors in young rats. We revealed a substantial decrease of GluN2B subunit expression in the hippocampus at P23 using Western blot analysis and real-time polymerase chain reaction assay. Moderate changes were also found in GluN1, GluN2A, and GluA1 mRNA expression. The LPS-treated rats exhibited decreased exploratory and locomotor activity in the open field test and the impairment of spatial learning in the Morris water maze. Behavioral impairments were accompanied by a significant reduction in long-term hippocampal synaptic potentiation. Our data indicate that LPS-treatment in the critical period for excitatory synapse maturation alters ionotropic glutamate receptor gene expression, disturbs synaptic plasticity, and alters behavior.

Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in humans, and is often developed after an initial precipitating brain injury. This form of epilepsy is frequently resistant to pharmacological treatment; therefore, the prevention of TLE is the prospective approach to TLE therapy. The lithium-pilocarpine model in rats replicates some of the main features of TLE in human, including the pathogenic mechanisms of cell damage and epileptogenesis after a primary brain injury. In the present study, we investigated changes in the properties of glutamatergic transmission during the first 3 days after pilocarpine-induced acute seizures in Wistar rats (PILO-rats). Using RT-PCR and electrophysiological techniques, we compared the changes in the temporal cortex (TC) and hippocampus, brain areas differentially affected by seizures. On the first day, we found a transient increase in a ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl d-aspartate (NMDA) receptors in the excitatory synaptic response in pyramidal neurons of the CA1 area of the dorsal hippocampus, but not in the TC. This was accompanied by an increase in the slope of input-output (I/O) curves for fEPSPs recorded in CA1, suggesting an enhanced excitability in AMPARs in this brain area. There was no difference in the AMPA/NMDA ratio in control rats on the third day. We also revealed the alterations in NMDA receptor subunit composition in PILO-rats. The GluN2B/GluN2A mRNA expression ratio increased in the dorsal hippocampus but did not change in the ventral hippocampus or the TC. The kinetics of NMDA-mediated evoked EPSCs in hippocampal neurons was slower in PILO-rats compared with control animals. Ifenprodil, a selective antagonist of GluN2B-containing NMDARs, diminished the area and amplitude of evoked EPSCs in CA1 pyramidal cells more efficiently in PILO-rats compared with control animals. These results demonstrate that PILO-induced seizures lead to more severe alterations in excitatory synaptic transmission in the dorsal hippocampus than in the TC. Seizures affect the relative contribution of AMPA and NMDA receptor conductances in the synaptic response and increase the proportion of GluN2B-containing NMDARs in CA1 pyramidal neurons. These alterations disturb normal circuitry functions in the hippocampus, may cause neuron damage, and may be one of the important pathogenic mechanisms of TLE.

Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats.

Temporal lobe epilepsy (TLE) is the most common type of epilepsy in humans. The lithium-pilocarpine model in rodents reproduces some of the main features of human TLE. Three-week-old Wistar rats were used in this study. The changes in AMPA receptor subunit composition were investigated in several brain areas, including the medial prefrontal cortex (mPFC), the temporal cortex (TC), and the dorsal (DH) and ventral hippocampus (VH) during the first week following pilocarpine-induced status epilepticus (PILO-induced SE). In the hippocampus, GluA1 and GluA2 mRNA expression slightly decreased after PILO-induced SE and returned to the initial level on the seventh day. We did not detect any significant changes in mRNA expression of the GluA1 and GluA2 subunits in the TC, whereas in the mPFC we observed a significant increase of GluA1 mRNA expression on the third day and a decrease in GluA2 mRNA expression during the entire first week. Accordingly, the GluA1/GluA2 expression ratio increased in the mPFC, and the functional properties of the pyramidal cell excitatory synapses were disturbed. Using whole-cell voltage-clamp recordings, we found that on the third day following PILO-induced SE, isolated mPFC pyramidal neurons showed an inwardly rectifying current-voltage relation of kainate-evoked currents, suggesting the presence of GluA2-lacking calcium-permeable AMPARs (CP-AMPARs). IEM-1460, a selective antagonist of CP-AMPARs, significantly reduced the amplitude of evoked EPSC in pyramidal neurons from mPFC slices on the first and third days, but not on the seventh day. The antagonist had no effects on EPSC amplitude in slices from control animals. Thus, our data demonstrate that PILO-induced SE affects subunit composition of AMPARs in different brain areas, including the mPFC. SE induces transient (up to few days) incorporation of CP-AMPARs in the excitatory synapses of mPFC pyramidal neurons, which may disrupt normal circuitry functions.