ABSTRACT
Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.
Subject(s)
Cognition/physiology , Cytoskeletal Proteins/genetics , Long-Term Synaptic Depression/genetics , Nerve Tissue Proteins/genetics , Neuronal Plasticity/genetics , RNA, Messenger/metabolism , Receptors, Metabotropic Glutamate/metabolism , Reversal Learning/physiology , Spatial Learning/physiology , Animals , Cytoskeletal Proteins/metabolism , Gene Knock-In Techniques , Long-Term Synaptic Depression/physiology , Mice , Mutation , Nerve Tissue Proteins/metabolism , Protein Transport , Proteolysis , Receptors, AMPA/metabolism , Time Factors , UbiquitinationABSTRACT
The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits. Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition.
Subject(s)
Cognition/physiology , Intracellular Signaling Peptides and Proteins/physiology , MAP Kinase Signaling System/physiology , Protein Serine-Threonine Kinases/physiology , Protein Transport/physiology , Receptors, Glutamate/physiology , Animals , Endocytosis/physiology , Female , Hippocampus/physiology , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/genetics , Long-Term Synaptic Depression/physiology , Male , Mice , Mice, Knockout , Models, Animal , Neuronal Plasticity/physiology , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/genetics , Synaptic Transmission/physiologyABSTRACT
Fear and anxiety behaviors are underpinned by neuronal changes within the amygdala. Here, the effects of exposure to natural and synthetic cat odor on behavior and amygdala plasticity were determined. Exposure to natural odor elicited typical and persistent anxiety-related behaviors, such as avoidance, freezing, and flat-back approach; however, synthetic odorant evoked no significant alteration in behavior. Furthermore, ex vivo induction of long-term potentiation within the medial nucleus of the amygdala, a principal area involved in olfactory perception, was significantly reduced after exposure to natural, but not synthetic, odor. Data presented here suggests that the synthetic odorant utilized may lack the constituents that are required to indicate predator presence in rodents and also the capacity to modulate neuronal plasticity within the medial nucleus of the amygdala.
Subject(s)
Amygdala/physiology , Anxiety/physiopathology , Avoidance Learning/physiology , Neuronal Plasticity/physiology , Odorants , Pheromones , Amygdala/drug effects , Animals , Anxiety/psychology , Avoidance Learning/drug effects , Cats , Male , Neuronal Plasticity/drug effects , Pheromones/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
Synchronized and rhythmic activity within the amygdala is thought to play a pivotal role in the generation of fear- and anxiety-related behaviour. The aim here was to determine the validity of the in vitro amygdala slice preparation to investigate the generation of rhythmic activity similar to that observed in vivo. Extracellular population activity recorded from the lateral nucleus of the amygdala in vitro showed significant enhancement of activity within the theta-band frequency (3-9 Hz) in the presence of kainic acid (100 nm; n=18). Alterations in the patterns of oscillatory activity within the gamma frequency band (20-40 Hz) were observed in the presence of (RS)-3,5-dihydroxyphenylglycine (10 microm; n=7) or carbachol (50 microm; n=5). Theta frequency oscillatory activity was blocked in the presence of the gap junction blocker carbenoxolone (100 mm), whereas gamma frequency oscillatory activity showed increased variability in the dominant frequency of rhythmic activity. The results suggest that the neuronal circuitry of the amygdala in vitro is capable of generating and sustaining rhythmic activity and that intercellular communication via gap junctions may play a role in the synchronization of population activity underlying this oscillatory activity.
Subject(s)
Amygdala/physiology , Biological Clocks/physiology , Gap Junctions/physiology , Neural Pathways/physiology , Neurons/physiology , Action Potentials/drug effects , Action Potentials/physiology , Amygdala/anatomy & histology , Amygdala/drug effects , Animals , Anti-Ulcer Agents/pharmacology , Biological Clocks/drug effects , Carbenoxolone/pharmacology , Cell Communication/drug effects , Cell Communication/physiology , Cholinergic Agonists/pharmacology , Cortical Synchronization/drug effects , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Gap Junctions/drug effects , Male , Neural Pathways/anatomy & histology , Neural Pathways/drug effects , Neurons/drug effects , Organ Culture Techniques , Rats , Rats, Wistar , Theta Rhythm/drug effectsABSTRACT
The amygdala receives multi-modal sensory inputs and projects to virtually all levels of the central nervous system. Via these widespread projections, the amygdala facilitates consolidation of emotionally arousing memories. How the amygdala promotes synaptic plasticity elsewhere in the brain remains unknown, however. Recent work indicates that amygdala neurons show theta activity during emotional arousal, and various types of oscillations during sleep. These synchronized neuronal events could promote synaptic plasticity by facilitating interactions between neocortical storage sites and temporal lobe structures involved in declarative memory.
