Altered short-term plasticity in the prefrontal cortex after early life seizures

Abstract

Seizures during development are a relatively common occurrence and are often associated with poor cognitive outcomes. Recent studies show that early life seizures alter the function of various brain structures and have long-term consequences on seizure susceptibility and behavioral regulation. While many neocortical functions could be disrupted by epileptic seizures, we have concentrated on studying the prefrontal cortex (PFC) as disturbance of PFC functions is involved in numerous co-morbid disorders associated with epilepsy. In the present work we report an alteration of short-term plasticity in the PFC in rats that have experienced early life seizures. The most robust alteration occurs in the layer II/III to layer V network of neurons. However short-term plasticity of layer V to layer V network was also affected, indicating that the PFC function is broadly influenced by early life seizures. These data strongly suggest that repetitive seizures early in development cause substantial alteration in PFC function, which may be an important component underlying cognitive deficits in individuals with a history of seizures during development.

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.