Abstract
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2−/− mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2−/− mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2−/− mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2−/− mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2−/− were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2−/− phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
Highlights
Lysophosphatidic acids (LPAs) strengthen glutamatergic synaptic neurotransmission and plasticity in the cortex and hippocampus via a presynaptic process involving an LPA receptor-2 (LPAR2)-evoked enhancement of glutamate release [1,2,3]
Excitability was similar in slices of young mice (Fig. 1b) but hippocampal network excitability was significantly lower in slices of middle-aged LPAR2−/− mice (≥ 50 weeks) as compared with the respective wild-type controls (Fig. 1c)
The present study shows that deficiency of the presynaptic LPAR2 is associated with (1) prevention of age-associated hippocampal hyperexcitability and enhancement of hippocampal long-term potentiation (LTP) in middle-aged mice, (2) higher accuracy and response velocity in tasks requiring high attention, (3) lower mere exploratory activity during non-active daytime and (4) lower expression of neuronal activity marker genes in resting naïve animals
Summary
Lysophosphatidic acids (LPAs) strengthen glutamatergic synaptic neurotransmission and plasticity in the cortex and hippocampus via a presynaptic process involving an LPA receptor-2 (LPAR2)-evoked enhancement of glutamate release [1,2,3]. LPAs can be generated within the synaptic cleft from lysophosphatidylcholines (LPC) of different chain lengths and saturation, via the ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) known as autotaxin, which was found in astrocytic processes ensheathing glutamatergic cortical and hippocampal synapses [5]. This localization is optimal for local regulation of excitatory cortical transmission owing to autotaxin’s ability to attach to activated membranes via integrins near its release site [6] and to recruit and prefer specific LPC species [7, 8], which are actively imported through the blood–brain barrier [9]. The above-described synaptic lipid-signaling loop was shown to regulate the cortical excitation–inhibition balance and sensory information processing [1, 3]
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