Environmental enrichment: Evidence for an unexpected therapeutic influence

Abstract

Environmental enrichment produces wide-ranging effects in the brain at molecular, cellular, network, and behavioral levels. The changes in neuronal plasticity are driven by changes in neurotransmitters, neurotrophic factors, neuronal morphology, neurogenesis, network properties of the brain, and behavioral correlates of learning and memory. Exposure to an enriched environment has also demonstrated intriguing possibilities for treatment of a variety of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and Parkinson's disease. The effect of environmental enrichment in epilepsy, a neurodegenerative disorder with pathological neuronal plasticity, is of considerable interest. Recent reports of the effect of environmental enrichment in the Bassoon mutant mouse, a genetic model of early onset epilepsy, provides a significant addition to the literature in this area.

Introduction

The epilepsies are a diverse group of neurological disorders defined by an unprovoked seizure and a brain which has an enduring predisposition to seizures (Fisher et al., 2014). In a recent issue of Experimental Neurology, Morelli et al. (2014) report on an electrophysiological and morphological analysis of the effects of environmental enrichment on the development and expression of epilepsy in mice with a mutation in the presynaptic protein Bassoon. They provide evidence that environmental enrichment influences functional and structural features of neural circuitry associated with epilepsy and its development in this model of epilepsy. The results of the study add to evidence that environmental experience can modify development and expression of a variety of disorders in the nervous system, and offer an intriguing clue about the powerful effects of environment on the structure and function of neural circuits.

Epilepsy is estimated to have a lifetime incidence of up to 5 per 1000 in developed countries and 2–3 fold greater in developing countries and affects nearly 70 million people worldwide (Ngugi et al., 2010). The impact of seizures in epilepsy has a magnified effect on the quality of life of those affected due to the unpredictability of the seizures, which can result in serious injury, limits activities, and often precludes driving. Epilepsy is also associated with significant social stigma, which can further limit employment and social interactions (Jacoby and Austin, 2007). Furthermore, cognitive deficits and mental health disorders are frequently seen as co-morbidities with epilepsy (LaFrance et al., 2008). Current pharmacological therapies fail to control seizures in 25–30% of individuals (Kwan and Brodie, 2000, Mattson et al., 1996), and despite the introduction of several new anti-seizure medications, some with novel mechanisms of action, the proportion of medically intractable cases has not changed (Boon et al., 2002, Cross and Riney, 2009, Leppik, 2002, Matsuo and Riaz, 2009). Additionally, pharmacologic anti-seizure medications are known to have a variety of significant adverse effects (Swann, 2001), including impairing cognitive functioning (Park and Kwon, 2008). Therefore significant effort is appropriately directed toward the identification of novel therapeutic approaches, including non-pharmacological approaches, for epilepsy.

Commonly the recurrent seizures of epilepsy are associated with a progressive neurodegenerative process. One of the most common forms of epilepsy in humans, temporal lobe epilepsy (TLE), has been demonstrated in numerous studies of humans and in animal models to be associated with the progressive development of structural and functional pathologies. Continued seizures in TLE are associated with progressive worsening of seizures (French et al., 1993), increasing resistance to anti-seizure medications (Kwan and Brodie, 2000), progressive damage to the hippocampus, amygdala, and entorhinal cortex (Bernasconi et al., 2005), as well as more wide-spread cerebral atrophy (Bernhardt et al., 2009). Neuropsychological deficits are more significant in those with a greater duration of TLE (Oyegbile et al., 2004). Animal studies utilizing various models of TLE have demonstrated cell death (Kotloski et al., 2002), development of aberrant connections including sprouting of mossy fibers, dentate granule cells (Cavazos et al., 1991), CA3 neurons (Siddiqui and Joseph, 2005), entorhinal cortex (Shetty, 2002), and anomalous migration of new cells (Houser, 1990, Parent et al., 1997) which progress with repeated seizures. Worsening deficits in learning and memory have also been demonstrated with an increasing number of seizures in a rat model of TLE (Kotloski et al., 2002).

While a significant proportion of those with TLE may have effective control of their seizures with medications, adverse side effects are common with many of these medications. For those whose seizures are pharmaco-resistant, surgical resection of the seizure focus may lead to control of the seizures, though surgical resection may also result in significant cognitive deficits (Spencer and Huh, 2008). Finally, a significant number of individuals are unable to control their seizures with either medications or surgery and they continue to suffer from chronic recurrent seizures. Additional therapeutic approaches are needed for these individuals.