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

Abstract

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.

The Synaptic Vesicle Glycoprotein 2: Structure, Function, and Disease Relevance

“…Recent work by Serrano et al showed that heterozygous SV2A knockout animals demonstrate altered habituation to novel environments, increased anxiety levels, and spatial memory deficits. No changes were observed in fear conditioning or locomotor behavior …”

“…No changes were observed in fear conditioning or locomotor behavior. 154 SV2s in Peripheral Nervous and Neuroendocrine Disorders. SV2 paralogues have been implicated in spinal muscular atrophy (SMA), the leading genetic cause of infant mortality.…”

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218

“…Mice that lack SV2A develop severe seizures and die within 3 weeks of birth 58 , whereas mice heterozygous for one functional copy of Sv2a have a normal lifespan, but develop an anxiety-like phenotype 50 . Conditional knockout mice with decreased SV2A in hippocampus are free of epileptic seizures but show elevated levels of anxiety, as measured with the Elevated Plus Maze 59 . Genetically epilepsy-prone rats exhibit an anxiety phenotype across multiple measures prior to having developed epileptic seizures 60 .…”

Marc Richelle (1930–2021) and the Study of Temporal Regulation of Behaviour in Animals

“…If Richelle was, at least in part, an accidental psychopharmacologist, he was certainly an active one, producing more than twenty articles on the subject, and work on psychopharmacology and behavioural neuroscience continues to this day in the laboratory he founded (e.g., Didone, van Ingelgom, Tirelli, & Quartemont, 2019 ; Serrano et al, 2019 ). However, as well as pharmacological work, in his early years Richelle also conducted some purely behavioural studies, and I will mention two of the more unusual ones.…”