Research Article: Anxiety-like features and spatial memory problems as a consequence of hippocampal SV2A expression

Date Published: June 5, 2019

Publisher: Public Library of Science

Author(s): Maria Elisa Serrano, Odile Bartholomé, Priscilla Van den Ackerveken, André Ferrara, Bernard Rogister, Alain Plenevaux, Ezio Tirelli, Giuseppe Biagini.


The Synaptic Vesicle Protein 2A (SV2A) is a transmembrane protein whose presence is reduced both in animal models and in patients with chronic epilepsy. Besides its implication in the epileptic process, the behavioural consequences of the changes in its expression remain unclear. The purpose of our research is to better understand the possible role(s) of this protein through the phenotype of cKO (Grik4 Cre+/-, SV2A lox/lox) mice, male and female, which present a specific decrease of SV2A expression levels in the hippocampal glutamatergic neurons but without any epileptic seizures. In this study, we compare the cKO mice with cHZ (Grik4 Cre+/-, SV2A lox/+) and WT (Grik4 Cre+/+, SV2A lox/lox) mice through a battery of tests, used to evaluate different features: the anxiety-related features (Elevated Plus Maze), the locomotor activity (Activity Chambers), the contextual fear-related memory (Contextual Fear Conditioning), and the spatial memory (Barnes Maze). Our results showed statistically significant differences in the habituation to a new environment, an increase in the anxiety levels and spatial memory deficit in the cHZ and cKO groups, compared to the WT group. No statistically significant differences due to the genotype appeared in the spontaneous locomotor activity or the fear-linked memory. However, sexual differences were observed in this last feature. These results highlight not only an important role of the SV2A protein in the cognitive and anxiety problems typically encountered in epileptic patients, but also a possible role in the symptomatology of other neurodegenerative diseases, such as the Alzheimer’s disease.

Partial Text

The SV2 protein family comprises three integral membrane paralogs: SV2A, SV2B, and SV2C. In spite of sharing approximately 60% of their sequences, these three isoforms are implicated in different pathologies, thus suggesting a specific role for each of them [1–4]. Amongst these isoforms, the most studied is the SV2A protein, due to its ubiquitous expression in the brain and its implication in epileptic disease (see hereunder). Beyond the initial suggestion of its role as a transporter of ions or neurotransmitters [5,6], the SV2A protein seems to act mainly as modulator of the synaptic transmission. The invalidation of this protein does not alter the morphology of the brain, the amount of synapses, or their structure [6,7]. However, its absence reduces the neurotransmission [8,9] and may induce an imbalance between glutamatergic and GABAergic levels [10–13]. Furthermore, three key findings have identified the SV2A protein as an all-important molecule involved in the epileptic process. Accordingly, the authors in [7,14] showed that homozygous SV2A KO mice displayed severe seizures at P7, and died in status epilepticus two to three weeks after birth. In humans, the homozygous mutation in SV2A has been also associated with intractable epilepsy, microcephaly, and developmental and growth retardation [15]. Moreover, SV2A has been proved to be the specific molecular target of new antiepileptic drugs, such as the levetiracetam [16] or the brivaracetam [17,18].

During the last few years, the SV2A protein has emerged as a possible key element to understand the epileptic disease. Indeed, when the SV2A gene is completely deleted, mice experience seizures starting seven days after birth and die in status epilepticus around day 15 [7,14]. Furthermore, this protein is the molecular target of one of the most prescribed antiepileptic drugs: the levetiracetam [16]. Despite the demonstrated relationship between a decrease in SV2A levels in epileptic foci and the presence of brain seizures, the potential implication of this protein in the cognitive problems exhibited by epileptic patients is barely known. The phenotyping of Grik4 Cre+/-, SV2A lox/lox (cKO) mice, exempt from spontaneous seizures [30], might therefore help us understand the role of this protein in the cognitive process associated with the hippocampus.

The phenotyping of Grik4 Cre+/-, SV2A lox/lox mice confirms a link between the decrease of the SV2A protein in the hippocampus, and the memory and anxiety-related problems detected in the chronic epilepsy. These results suggest a possible implication of the SV2A protein in anxiety or memory disorders, such as the post-traumatic stress disorder or the Alzheimer’s disease.