Epac2 Mediates cAMP-Dependent Potentiation of Neurotransmission in the Hippocampus.

Presynaptic terminal cAMP elevation plays a central role in plasticity at the mossy fiber-CA3 synapse of the hippocampus. Prior studies have identified protein kinase A as a downstream effector of cAMP that contributes to mossy fiber LTP (MF-LTP), but the potential contribution of Epac2, another cAMP effector expressed in the MF synapse, has not been considered. We investigated the role of Epac2 in MF-CA3 neurotransmission using Epac2(-/-) mice. The deletion of Epac2 did not cause gross alterations in hippocampal neuroanatomy or basal synaptic transmission. Synaptic facilitation during short trains was not affected by loss of Epac2 activity; however, both long-term plasticity and forskolin-mediated potentiation of MFs were impaired, demonstrating that Epac2 contributes to cAMP-dependent potentiation of transmitter release. Examination of synaptic transmission during long sustained trains of activity suggested that the readily releasable pool of vesicles is reduced in Epac2(-/-) mice. These data suggest that cAMP elevation uses an Epac2-dependent pathway to promote transmitter release, and that Epac2 is required to maintain the readily releasable pool at MF synapses in the hippocampus.

Hippocampal metaplasticity is required for the formation of temporal associative memories.

Metaplasticity regulates the threshold for modification of synaptic strength and is an important regulator of learning rules; however, it is not known whether these cellular mechanisms for homeostatic regulation of synapses contribute to particular forms of learning. Conditional ablation of mGluR5 in CA1 pyramidal neurons resulted in the inability of low-frequency trains of afferent activation to prime synapses for subsequent theta burst potentiation. Priming-induced metaplasticity requires mGluR5-mediated mobilization of endocannabinoids during the priming train to induce long-term depression of inhibition (I-LTD). Mice lacking priming-induced plasticity had no deficit in spatial reference memory tasks, but were impaired in an associative task with a temporal component. Conversely, enhancing endocannabinoid signaling facilitated temporal associative memory acquisition and, after training animals in these tasks, ex vivo I-LTD was partially occluded and theta burst LTP was enhanced. Together, these results suggest a link between metaplasticity mechanisms in the hippocampus and the formation of temporal associative memories.

Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning.

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility.

Genetic disruption of Grm5 causes complex alterations in motor activity, anxiety and social behaviors.

Autism is a neurodevelopmental disorder characterized by impaired social interactions and restricted and repetitive behaviors. Although group 1 metabotropic glutamate receptors (mGluRs), and in particular mGluR5, have been extensively proposed as potential targets for intervention in autism and other neurodevelopmental disorders, there has not been a comprehensive analysis of the effect of mGluR5 loss on behaviors typically assessed in autism mouse models thought to be correlates of behavioral symptoms of human disorders. Here we present a behavioral characterization of mice with complete or partial loss of mGluR5 (homozygous or heterozygous null mutations in Grm5 gene). We tested several autism related behaviors including social interaction, repetitive grooming, digging and locomotor behaviors. We found that digging and marble burying behaviors were almost completely abolished in mGluR5 ko mice, although self-grooming was not altered. Social interaction was impaired in ko but not in heterozygote (het) mice. In tests of locomotor activity and anxiety related behaviors, mGluR5 ko mice exhibited hyperactivity and reduced anxiety in the open field test but unexpectedly, showed hypoactivity in the elevated zero-maze test. There was no impairment in motor learning in the accelerating rotarod in both ko and het mutant. Together these results provide support for the importance of mGluR5 in motor and social behaviors that are specifically affected in autism disorders.