Altered short-term plasticity in the prefrontal cortex after early life seizures
Highlights
► Sixty-five early life seizures administered to rat pups in the second postnatal week. ► Three forms of short-term plasticity are assessed in 2 networks in the prefrontal cortex. ► Post-tetanic potentiation increases in both prefrontal networks. ► Activity-dependent plasticity decreases in only LII-LV networks. ► This suggests a network disruption that may account for cognitive deficits after ELS.
Introduction
The first year of life is associated with a high incidence of seizures (Garfinkle and Shevell, 2011, Hauser, 1992, Hauser, 1994, Heide et al., 2011), and seizures during this crucial time in neurodevelopment are often associated with serious adverse neurological consequences that persist into adulthood (Brunquell et al., 2002, Holmes, 2009). Children who have experienced early life seizures (ELS) are at increased risk for cognitive impairments and behavioral disorders (Holmes, 2009). Depression, anxiety, hyperactivity and deficits in attention are common psychiatric problems in children with epilepsy. The level of alteration of behavior and cognitive performance depends on the age of seizure onset, type, number and severity of epileptic episodes (Hoare, 1984, Seidenberg et al., 1986). An earlier age of onset and longer seizure duration correlate with poor learning ability and memory function (Hermann et al., 2002, Kaaden and Helmstaedter, 2009, Kent et al., 2006).
The hippocampo–prefrontal cortex circuit plays an important role in various aspects of learning and memory, such as consolidation of information and working memory (Laroche et al., 2000). Anatomical and electrophysiological studies have shown direct connections between hippocampus and medial PFC and the importance of proper functioning of both regions for memory processing (Jay et al., 1992, Tierney et al., 2004, Wall and Messier, 2001). Clinical and experimental studies have demonstrated alterations in working memory function due to epileptic seizures (Abrahams et al., 1999, Grippo et al., 1996, Kleen et al., 2011b). Studies show that in animals that have experienced recurrent seizures in early development, there are pathological alterations in synaptic organization (Holmes et al., 1998, Huang et al., 1999) and synaptic transmission (Isaeva et al., 2006) in the hippocampal network that parallel deficits in spatial learning and memory (Huang et al., 1999, Karnam et al., 2009, Liu et al., 1999). Even a single episode of neonatal seizures can permanently alter glutamate receptor expression in the CA1 region of hippocampus and impair working memory (Cornejo et al., 2007, Cornejo et al., 2008). As the CA1 region of hippocampus has direct projections to mPFC, one could expect that alterations in the hippocampus due to ELS by itself or through modification of information flowing to the mPFC may explain an impairment of working memory in rats that have experienced seizures in early development. On the other hand several studies show that modulation of mPFC activity and lesions in restricted areas of PFC can exert a major influence on memory and cognitive processes (Delatour and Gisquet-Verrier, 1996, Delatour and Gisquet-Verrier, 2000, Dias and Aggleton, 2000, Granon and Poucet, 1995, Granon et al., 1994, Lacroix et al., 2002, Ragozzino et al., 1999a, Ragozzino et al., 1999b).
The preponderance of clinical and animal data strongly indicates that neonatal seizures lead to substantial deficits that are associated with frontal cortical dysfunction. We have recently shown that animals experienced ELS have a deficit in behavioral flexibility associated with changes in prefrontal cortical (PFC) architecture (Kleen et al., 2011a), but the mechanisms underpinning this behavioral finding remain uncertain. Like many regions in the CNS, the PFC exhibits plasticity on both long and short timescales (Hempel et al., 2000). Short-term plasticity (STP) in particular is thought to be critically important for many of the functions of the PFC including short-term working memory (Mongillo et al., 2008) and information processing (Abbott and Regehr, 2004), and more recently it has been implicated in decision-making processes (Curtis and Lee, 2010, Deco et al., 2010, Rotman et al., 2011). Numerous computer-modeling studies of STP in neuronal circuits predict that alterations in STP could lead to cognitive deficits, and further evidence for the importance of STP comes from various disease models in which alterations in STP coincide with cognitive deficits (Deng et al., 2011, Ishizaki et al., 2000, Sakane et al., 2006, Schoch et al., 2002).
In the present study we used the flurothyl model of ELS to investigate the influence of neonatal seizures on excitatory signaling in LV pyramidal cells, the major output neurons of the PFC, and possible alteration in STP by ELS. The apical dendrites of LV neurons receive feedback information from thalamic inputs as well as information from cortico–cortical connections in layer II/III (LII/III) (Kuroda et al., 1996, Kuroda et al., 1998, Szentagothai, 1978). Their basal dendrites are heavily innervated by the hippocampus and form an interconnected network of deep pyramidal neurons whose continued firing during the delay phase of a working memory task is thought to underlie short-term working memory (Goldman-Rakic, 1995). Since both networks contribute to cognitive processes that are impaired in patients with a history of ELS and there is evidence that STP in LII/III-to-LV and LV-to-LV networks is modulated differently (Young and Yang, 2005), we chose to study STP in these two networks individually. Our data show that recurrent seizures early in development affect STP in LII/III-to-LV and LV-to-LV networks in LV PFC neurons.
Section snippets
Animals
All experiments were performed in accordance with the guidelines set down by the National Institute of Health and Dartmouth Medical School for the humane treatment of animals. The animal protocol was approved by the Institutional Animal Care and Use Committee of Dartmouth College. Sprague–Dawley rats (n = 9) were subjected to a total of 62–65 flurothyl-induced seizures from postnatal day (P) 6 to P16 using previously described methods (Karnam et al., 2009, Kleen et al., 2011b, Lucas et al., 2011
ELS does not alter basal evoked excitatory synaptic transmission
In the first set of experiments we estimated the effect of ELS on basal evoked excitatory synaptic transmission in both, LII/III-to-LV and LV-to-LV networks separately (Figs. 1A and B). Stimulation of LII/III or LV of mPFC evoked fEPSPs in LV in all slices from flurothyl treated and littermate control animals. fEPSP amplitude was not different between control (172.6 ± 14.2 μV in LII/III-to-LV; 159.2 ± 14.2 μV in LV-to-LV) and ELS (163.1 ± 10.6 μV in LII/III-to-LV; 167.6 ± 14.2 μV in LV-to-LV) groups,
Discussion
The main finding of the current study is that early life generalized seizures alter STP in the prefrontal cortex. The alterations in STP suggest changes in processing of information and “online” modulation of neural circuits, which may play a contributing role in the behavioral and cognitive comorbidities (Brooks-Kayal, 2010, Cabaleiro, 1969, Levin and Duchowny, 1991, Dunn et al., 2003, Kaufmann et al., 2009) that occur after ELS in children, and may also relate to the deficits in behavioral
Conclusions
We used a flurothyl animal model of early life seizures to show alteration of STP in the PFC. This model shows cognitive deficits in both a hippocampal-dependent task (Huang et al., 1999) as well as PFC-dependent tasks (Kleen et al., 2011a, Kleen et al., 2011b), but thus far there was no direct study elucidating the outcomes of ELS on PFC function. Given the importance of STP for information processing (Deng and Klyachko, 2011, Rotman et al., 2011), the findings shown here suggest that ELS may
Acknowledgments
This work was supported by National Institutes of Health grants RO1NS056170 and RO1NS041595 and Emmory R. Shapses research fund (GLH); Great Ormond Street Hospital Children's Charity (RCS); and the State Foundation of Fundamental Research of Ukraine F46.2/001 (EI).
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