The Correlation Between The Functional Activity Of Gabaergic Neurons In The Entorhinal Cortex And Schizophrenia-Like Behavior In Rats

【Objective】To investigate the relation between the subregions of the entorhinal cortex and schizophrenia-like behaviour,the effects of the local infusion GABA receptor agonist or antagonist into the medial or lateral entorhinal cortex on rat’s behavioral were demonstrated.【Method】270 g Sprague Dawley rats underwent stereotactic surgery on the brain,bilaterally implanted in a custom cannula to the medial entorhinal cortex or lateral entorhinal cortex.One week after surgery,three groups including MEC,LEC and the control group(VEH)were administered different treatments :(1)local infusion of γ-aminobutyric acid receptor agonist-muscimol(1 μg / 0.5 μL / side)to the LEC and MEC group;(2)local infusion of γ-aminobutyric acid receptor antagonist-picrotoxin(0.15 μg / 0.5 μL / side)to the LEC group and MEC group,and the control group was infused locally with the same amount of saline.30 min after infusion,a battery of behavioral tests was conducted,including open field test,elevated plus maze,startle response and prepulse inhibition,shuttle box avoidance,as well as Morris water maze.After behavioral tests,the rats were sacrificed and removed the brain.Then the fixed brains were cut into coronal section on vibratome and the latter were stained with cresyl violet to verification of cannula placements.In addition,in order to examine whether local infusion of the medial entorhinal cortex or the lateral entorhinal cortex would alter neuronal activation in the brain,especially multiple regions receiving inputs from the medial entorhinal cortex or lateral entorhinal cortex,the expression and distribution of the immediate early gene c-Fos in the brain were measured after infusion.【Result】(1)Local infusion of muscimol: The open field test indicated that the total distance moved in the MEC group was higher than that of the VEH group(P < 0.05),but not the LEC group,suggesting that the locomotor activity increased after activating the GABAergic neurons of the MEC.In the elevated plus maze,the time spent in the open arms and the frequency entered in the open arms were higher in the MEC group and the LEC group compared with the VEH group(P < 0.05),indicated the effect of the anti-anxious.In the prepulse inhibition,the LEC startle reactivity was decreased(P < 0.05),and the %PPI of the MEC group was significantly lower than that of the VEH group(P < 0.05),reflected the impaired sensorimotor gating.In the shuttle box avoidance,the latency to avoid the foot shock was increase in the MEC and LEC group during the acquisition and retention(P < 0.05)and the number of active avoidances was decreased(P < 0.05),suggested that the learning and memory of the active avoidance was disrupted.In the Morris water maze,the MEC group revealed higher latency and longer distance moved(P < 0.05)to seek the hidden platform(P < 0.05),while the LEC group not.Moreover,the velocity of the three experiment groups was no different.In the reversal learning of the water maze,both LEC group and MEC group showed an increased latency(P < 0.05)and increased swimming distance(P < 0.05).Furthermore,c-Fos results showed MEC group or LEC infusion have widespread effects on cortical activity.(2)Local infusion of picrotoxin: In the open field test,the total distance moved for the MEC group was higher than that of the VEH group(P < 0.05).In the elevated plus maze,the MEC group spent more time in the open arms and have more entries in the open arms(P < 0.05)which indicated the effect of anti-anxious,but not the LEC group.In prepulse inhibition experiment,the MEC group showed higher %PPI than the VEH group(P < 0.05),suggesting the altered sensorimotor gating,but not the LEC group.In the shuttle box avoidance,the latency to avoid the foot shock was decreased in the MEC group(P < 0.05)and the number of active avoidances was higher than that of the VEH group during the acquisition(P < 0.05).So does the LEC group on a shorter latency during the acquisition(P < 0.05).But the three groups did not show any significant difference in the retention test.In the Morris water maze test,the MEC and LEC group showed an increased latency to find the hidden platform(P < 0.05)after local infusion,as well the longer swimming distance(P < 0.05).In the reversal learning of the water maze,the latency to search the re-located hidden platform was increased in the MEC group(P < 0.05),and the total swimming distance was also higher(P < 0.05),but not for the LEC group,when compared with the VEH group.Similarly,the c-Fos expression results indicated that the infusion of picrotoxin into both the MEC and the LEC group showed widespread effects on cortical activity.【Conclusion】(1)Local injection of muscimol: After infusion of muscimol,the excitatory / inhibition balance of the MEC and LEC was broken,resulting in impaired sensorimotor gating,enhanced spontaneous activity,anti-anxiety-like behavior,impaired the learning and memory of active avoidance and spatial navigation in the MEC.The rats in the LEC group showed anti-anxiety behaviors and impaired the active avoidance and spatial learning and memory.Both excited GABAergic neurons activity in the MEC and LEC relate with the schizophrenia-like behavior.(2)Local injection of picrotoxin: infusion of picrotoxin,the MEC group showed hyperactivity,altered sensorimotor gating,anxiolytic-like behavior,impaired spatial navigation,but improved acquisition of the active avoidance.The LEC group also had anti-anxiety-like behaviors,impaired part of the spatial navigation learning and memory ability,improved acquisition of the active avoidance of learning and memory.Both hypoactivity GABAergic neurons in the MEC and LEC induced the schizophrenia-like behavior.