Effects of Chronic Stress and Phenytoin on the Long-term Potentiation (LTP) in Rat Hippocampal CA1 Region

Abstract

To investigate the changes of LTP in hippocampal CA1 region induced by chronic stress and the effect of phenytoin on them, thirty-two adult male Sprague-Dawley rats were randomly divided equally into four groups: control group, control-phenytoin group, stress-saline group and stress-phenytoin group. Isolated hippocampal slices of rats were used to observe the changes of long-term potentiation (LTP) in hippocampal CA1 field using electrophysiological technique. Amplitude of population spike (PS) and field excitatory postsynaptic potentials (fEPSPs) slope were used to indicate the changes of LTP. High-frequency stimulation (HFS) was applied to Schaffer collaterals of hippocampal CA3 field, and the changes of PS amplitude and fEPSPs slope in CA1 field were observed. The results showed that the LTP induction rate, the increases of PS amplitude and fEPSPs slope after HFS in control and stress-phenytoin groups were significantly greater than those in stress-saline group (P<0.05). There were no significant differences between control group and stressphenytoin group or between control and control-phenytoin groups in these indexes (P>0.05). It is suggested that chronic stress can damage the development of LTP in hippocampal CA1 field, while phenytoin can protect the LTP of stressed hippocampal slices in normal state. Key wordsphenytoin; long-term potentiation; hippocampus; stress Stress is the response to stimulation from inside and outside with complicated effects on organisms. Appropriate stressful reactions are helpful in resisting diseases by activating unspecific modulation system, while severe or prolonged stresses are harmful and even induce mental and physical disorders such as recurrent depression, posttraumatic stress disorder (PTSD), Alzheimer's disease and epilepsy [1]. Hippocampus, a main brain region of key importance for learning, memory and emotion, is the target of stressful hormone and mediates stress response. It has plasticity and is liable to be impaired during chronic stress and participates in the pathology of some stress-related diseases that markedly affect memory and other cognitive functions [2,3]. Exploring the effects of stress on hippocampal functions can help to reveal pathogenesis of stress-related disorders.Long-term potentiation (LTP), a persistent increase in the efficacy of synaptic connections induced by high-frequency stimulation (HFS), has been regarded as a model of synapse plasticity. LTP in the hippocampus is especially related to learning and memory. Most scholars consider that Ca 2+ entering into the postsynaptic cells triggers the development of LTP [4][5][6]. Excitation of presynapses induces release of excitatory amino acid (EAA), which facilitates the Ca provokes a series of physiochemical reactions and induces LTP. It has been reported that exposure to stressful event can impair the induction of LTP in the hippocampus [7][8][9]. However, the mechanisms of LTP suppression under stress have not been fully elucidated.Phenytoin, an anti-epileptic drug, can decrease the...

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…Irrespective of the models that have been used, chronic overexposure to stress hormones has generally been found to reduce the ability to induce or maintain LTP and to enhance the likelihood to induce LTD, even when circulating corticosteroid levels at the time of recording were very low. This was observed for projections to the (dorsal) hippocampal CA1 area (Bodnoff et al, 1995;Gerges et al, 2001;Von Frijtag et al, 2001;Alfarez et al, 2003;Zheng et al, 2004;Aleisa et al, 2006a,b,c;Artola et al, 2006;Krugers et al, 2006;Holderbach et al, 2007;Ma et al, 2007;Srivareerat et al, 2009;Kamal et al, 2010;Sterlemann et al, 2010;Tran et al, 2011), the CA3 area (Kole et al, 2002(Kole et al, , 2004Pavlides et al, 2002;Maggio and Segal, 2011), the PFC (Cerqueira et al, 2007;Goldwater et al, 2009;Lee and Goto, 2011;Lee et al, 2011b;Quan et al, 2011a,b;Zhang et al, 2011), and the bed nucleus stria terminalis (Conrad et al, 2011). The reverse, however, was seen in the ventral-most part of the hippocampus (Maggio and Segal, 2011).…”

“…Some 922 of the above-mentioned studies demonstrated that particular molecules are critical for the electrophysiological changes to occur, such as calcineurin and Ca 2ϩ /calmodulin-dependent protein kinase II (Aleisa et al, 2006a,b,c), NR2B subunits, inhibitor of nuclear factor-B (Christoffel et al, 2011), and brain-derived neurotrophic factor (Zhou et al, 2000;Radecki et al, 2005;Aleisa et al, 2006c). Compounds that prevented or normalized the development of changes in neural activity include nicotine (Aleisa et al, 2006a,b,c), antidepressants (Von Frijtag et al, 2001;Kole et al, 2002Kole et al, , 2004Kessal et al, 2006;Holderbach et al, 2007;Wang et al, 2010;Holm et al, 2011), ketamine (Li et al, 2011), memantine (Quan et al, 2011), antiglucocorticoids Karst and Joëls, 2007;Spyrka and Hess, 2010), and phenytoin (Zheng et al, 2004), whereas ␤-amyloid exacerbated the effects of chronic stress (Srivareerat et al, 2009;Tran et al, 2011). However, it is unclear whether these compounds 1) directly interfere with chronic-stress-dependent signaling pathways, 2) tap indirectly into the same pathways, or 3) compensate for/ counteract the effects of chronic stress through independent mechanisms.…”

“…Although the consequences of chronic stress for various behavioral tasks have been addressed in detail in numerous studies (for reviews, see Shors, 2006;Conrad, 2010;Marin et al, 2011), we here highlight only those studies combining electrophysiological measurements with behavioral performance. These showed that chronic stress reduces hippocampal synaptic plasticity in parallel with impaired spatial memory, including the reversal learning aspect (Bodnoff et al, 1995;Zheng et al, 2004;Aleisa et al, 2006a;Ma et al, 2007;Quan et al, 2011a,b), even many months after stress exposure (Sterlemann et al, 2010). Chronic stress also exacerbates cognitive decline due to amyloid-␤ treatment (Srivareerat et al, 2009;Tran et al, 2011).…”

The multimodal prospects for neuroprotection and disease modification in epilepsy: Relationship to its challenging neurobiology

“…Valproic acid (VPA) had shown efficacy against spontaneous seizures and deficits in visuospatial learning in KA models when given at the chronic phase to KA but not pilocarpine models (Pitkanen and Kubova, 2004). Carbamazepine (CBZ) and phenytoin (PHT) but not ethosuximide (ETS) had shown efficacy against spontaneous seizures when administered at the chronic phase in pilocarpine model (Watanabe et al, 1992;Ambrosio et al, 2000;Zhang et al, 2004b). Topiramate (TPM) showed the ability to protect hippocampal mitochondria against an external Ca ++ challenge (in CA1 and CA3 pyramidal subfields) when given at the chronic phase.…”

Neuronal plasticity: implications in epilepsy progression and management

“…It is used as prophylaxis after brain injury [Hernandez, 1997]. Phenytoin prevented stress-induced reductions in CA3 apical dendritic length and branch point numbers [Watanabe et al, 1992] and prevented stress-induced LTP blockade [Zhang et al, 2004]. PHT may however induce brain injury through peroxidation of neuronal membrane lipids initiated by free radical-generating mechanisms [Willmore and Triggs, 1984].…”