Prelimbic of Medial Prefrontal Cortex GABA Modulation through Testosterone on Spatial Learning and Memory.

Prefrontal cortex (PFC) is involved in multiple functions including attentional processes, spatial orientation, short-term memory, and long-term memory. Our previous study indicated that microinjection of testosterone in CA1 impaired spatial learning and memory. Some evidence suggests that impairment effect of testosterone is mediated by GABAergic system. In the present study, we investigated the interaction of testosterone (androgenic receptor agonist) and bicuculline (GABAA receptor antagonist) on spatial learning and memory performance in the prelimbic (PL) of male Wistar rats. Cannulae were bilaterally implanted into the PL region of PFC and drugs were daily microinjected for two minutes in each side. There are 4 experiments. In the first experiment, three sham groups were operated (solvent of testosterone, bicuculline, testosterone plus bicuculline). In the second experiment, different doses of testosterone (40, 80 µg /0.5 µL DMSO/each side) were injected into the PL before each session. In the third experiment, intra PL injections of bicuculline (2, 4 µg/0.5 µL DMSO/each side) were given before every session. In the last experiment, testosterone (80µg/0.5 µL DMSO/each side) along with bicuculline (2 µg/0.5 µL DMSO/each side) was injected into the PL. The results showed there is no difference between control group and sham operated group. Testosterone 80 µg and bicuculline 2 µg, each given separately, and also in combination increased escape latency to find the platform compared to the sham operated and cause to impaired spatial learning and memory. It is shown that intra PL microinjection of bicuculline after testosterone treatment could not rescue the spatial learning and memory impaired induced by testosterone.

Long-term increases in BK potassium channel underlie increased action potential firing in dentate granule neurons following pilocarpine-induced status epilepticus in rats.

Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy in adult. Since dentate gyrus granule cells (GCs) play a critical role in hippocampal seizure generation, it is, therefore, important to understand changes in intrinsic properties of GCs in TLE. In this study, the electrophysiological properties of GCs obtained from epileptic rates were compared with the control group using whole cell patch-clamp recording. Results indicated a significant increase in the number of action potentials (APs) in depolarizing currents of 150 pA, 200 pA, and 250 pA. In addition, there was a significant decrease in AP half-width of GCs. The amplitude of fast afterhyperpolarization (fAHP) in epileptic group significantly decreased compared to control group. Blockade of large conductance calcium activated potassium channel (BK), channels with paxilline and iberiotoxin reversed pilocarpine-induced changes in electrophysiological properties of GCs in epileptic group. These results suggest that the BK channel blockers by reversing the firing properties of GCs might have beneficial preventative effects on pilocarpine-induced electrophysiological changes.

The effect of paxilline on early alterations of electrophysiological properties of dentate gyrus granule cells in pilocarpine-treated rats.

The dentate gyrus of hippocampus has long been considered as a focal point for studies on mechanisms responsible for the development of temporal lobe epilepsy (TLE). Change in intrinsic properties of dentate gyrus granule cells (GCs) has been considered as an important factor responsible in temporal lobe seizures. In this study, we evaluated the intrinsic properties of GCs, during acute phase of seizure (24 h after i.p. injection of pilocarpine) compared to sham group using whole cell patch-clamp recordings. Our results showed a significant increase in the number of action potentials (APs) after applying depolarizing currents of 200 pA (p < 0.01) and 250pA (p < 0.05) compared to sham group. The evaluation of AP properties revealed a decrease in half-width of AP in GCs of seizure group (1.27 ± 0.03 ms) compared to sham group (1.60 ± 0.11). Moreover, addition of BAPTA to pipette solution prevented changes in AP half-width in seizure group (1.71 ± 0.11 ms) compared to sham group (1.91 ± 0.08 ms). In contrast, an increase in the amplitude of fast afterhyperpolarization was observed in GCs of seizure group (-11.68 ± 0.72 mV) compared to sham group (-8.28 ± 0.59 mV). Also, GCs of seizure group showed a significant increase in both firing rate and instantaneous firing frequency at depolarizing currents of 200 pA (P < 0.01) and 250 pA (P < 0.05) compared to sham group. The changes in electrophysiological properties of GCs were attenuated after bath application of paxilline suggesting possible involvement of large conductance Ca(2+)- activated K(+) channel (BK channel). Our results suggested the possible involvement of certain potassium channels in early changes of intrinsic properties of GCs which eventually facilitate TLE development.

L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats.

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (Aß) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of Aß pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The Aß 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after Aß injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30 µg/2 µl) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, Aß treated rats showed delayed acquisition in a spatial reference memory task. Aß treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30 µg but not 3 µg) and nimodipine (30 µg). Calpain 2, caspase 12 and 3 were increased in the Aß treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease.