Environmental enrichment restores CA1 hippocampal LTP and reduces severity of seizures in epileptic mice

Abstract

We have analyzed the effects of environmental enrichment (EE) in a seizure-prone mouse model in which the genetic disruption of the presynaptic protein Bassoon leads to structural and functional alterations in the hippocampus and causes early spontaneous seizures mimicking human neurodevelopmental disorders. One-month EE starting at P21 reduced seizure severity, preserved long-term potentiation (LTP) and paired-pulse synaptic responses in the hippocampal CA1 neuronal population and prevented the reduction of spine density and dendrite branching of pyramidal neurons. These data demonstrate that EE exerts its therapeutic effect by normalizing multiple aspects of hippocampal function and provide experimental support for its use in the optimization of existent treatments.

Introduction

Early onset recurrent epilepsy is often associated with cognitive deficit during development and in the adult age. However, also chronic antiepileptic treatments can induce per se hippocampal damage and impair learning and memory processes in experimental animals and humans (Meador et al., 2007, Mula and Trimble, 2009, Sgobio et al., 2010, Wu and Wang, 2002). Adult mice lacking the presynaptic protein Bassoon (bsn) display early onset epilepsy (Altrock et al., 2003, Ghiglieri et al., 2009) associated with widespread brain alterations, including structural abnormalities and reduced synaptic plasticity in the hippocampus (Heyden et al., 2011, Sgobio et al., 2010). Bsn is a member of a complex cytomatrix of proteins exclusively assembled at the presynaptic active zones that plays a key role in the organization of synaptic vesicles cycle regulating neurotransmitter release (Altrock et al., 2003, Takei et al., 1996, tom Dieck et al., 1998). For the relevant role of bsn in the development and function of highly specialized synapses at auditory hair cells and retinal photoreceptors (Dick et al., 2001, Khimich et al., 2005) mutant bsn mice also display reduced visual capabilities (Goetze et al., 2010) and impaired sound encoding (Jing et al., 2013), mimicking genetic neurodevelopmental disorders characterized by epilepsy, mental retardation, and sensory deficits (Tavyev Asher and Scaglia, 2012).

Early treatment of newborn mutant bsn mice with an antiepileptic drug is able to reduce epileptic seizures and restore hippocampal long-term potentiation (LTP) but it does not prevent the loss of spine density in hippocampal neurons and exerts per se detrimental effects on the morphology of CA1 pyramidal cells in healthy mice (Sgobio et al., 2010).

Environmental enrichment (EE), an experimental setting where the animal housing condition provides a combination of cognitive, motor and social stimulation relative to standard housing, improves a variety of hippocampal-dependent functions (Laviola et al., 2008, Nithianantharajah and Hannan, 2006) and has a therapeutic potential in treating epilepsy (Dhanushkodi and Shetty, 2008) with reduced side effects. Animals exposed to EE show increased synaptic density in comparison to control subjects (Faherty et al., 2003, Nithianantharajah and Hannan, 2006) and augmented synaptic strength in the CA1 hippocampal region (Foster and Dumas, 2001, Foster et al., 1996, Green and Greenough, 1986). However, studies investigating the effect of EE on hippocampal function have produced mixed results, also due to the variability in the behavioral protocols employed to test its efficacy. Here we examined whether EE was effective in slowing the progression of seizure severity in epileptic mutant bsn mice and in preserving hippocampal morphology and plastic functions.