The importance of having Arc: expression of the immediate-early gene Arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptor antagonism.

Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning.

A robust activity marking system for exploring active neuronal ensembles.

Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system's versatility.

The contribution of GABAergic dysfunction to neurodevelopmental disorders.

GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. The GABAergic system is indispensable for maintaining the balance between excitation and inhibition (E/I balance) required for normal neural circuit function. E/I imbalances that result from perturbations in the development of this system, ranging from the generation of inhibitory neurons to the formation of their synaptic connections, have been implicated in several neurodevelopmental disorders. In this review, we discuss how impairments at different stages in GABAergic development can lead to disease states. We also highlight recent studies which show that modulation of the GABAergic system can successfully reverse cognitive deficits in disease models and suggest that therapeutic strategies targeting the GABAergic system could be effective in treating neurodevelopmental disorders.

Npas4 regulates a transcriptional program in CA3 required for contextual memory formation.

The rapid encoding of contextual memory requires the CA3 region of the hippocampus, but the necessary genetic pathways remain unclear. We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning. Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice. By recruiting RNA polymerase II to promoters and enhancers of target genes, Npas4 regulates a learning-specific transcriptional program in CA3 that includes many well-known activity-regulated genes, which suggests that Npas4 is a master regulator of activity-regulated gene programs and is central to memory formation.