ABSTRACT
Fear memories are acquired through neuronal plasticity, an orchestrated sequence of events regulated at circuit and cellular levels. The conventional model of fear acquisition assumes unimodal (for example, excitatory or inhibitory) roles of modulatory receptors in controlling neuronal activity and learning. Contrary to this view, we show that protease-activated receptor-1 (PAR1) promotes contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein-coupling partners. In the basolateral amygdala of fear-naive mice PAR1 couples to Gαq/11 and Gαo proteins, while after fear conditioning coupling to Gαo increases. Concurrently, stimulation of PAR1 before conditioning enhanced, but afterwards it inhibited firing of basal amygdala neurons. An initial impairment of the long-term potentiation (LTP) in PAR1-deficient mice was transformed into an increase in LTP and enhancement of fear after conditioning. These effects correlated with more frequent 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor-mediated miniature post synaptic events and increased neuronal excitability. Our findings point to experience-specific shifts in PAR1-G protein coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear.
Subject(s)
Amygdala/physiology , Fear/physiology , Long-Term Potentiation/physiology , Receptor, PAR-1/physiology , Amygdala/chemistry , Animals , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Fear/drug effects , Freezing Reaction, Cataleptic/drug effects , Freezing Reaction, Cataleptic/physiology , GTP-Binding Protein alpha Subunits, Gq-G11/physiology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Long-Term Potentiation/drug effects , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Miniature Postsynaptic Potentials/drug effects , Miniature Postsynaptic Potentials/physiology , Nerve Net/drug effects , Nerve Net/physiology , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/physiology , Pain Threshold , Patch-Clamp Techniques , Pyrroles/pharmacology , Quinazolines/pharmacology , Receptor, PAR-1/antagonists & inhibitors , Receptor, PAR-1/deficiency , Receptor, PAR-1/genetics , Recognition, Psychology/drug effects , Recognition, Psychology/physiologyABSTRACT
Integrins play key roles in the developing and mature nervous system, from promoting neuronal process outgrowth to facilitating synaptic plasticity. Recently, in hippocampal pyramidal neurons, ß3 integrin (ITGß3) was shown to stabilise synaptic AMPA receptors (AMPARs) and to be required for homeostatic scaling of AMPARs elicited by chronic activity suppression. To probe the physiological function for ITGß3-dependent processes in the brain, we examined whether the loss of ITGß3 affected fear-related behaviours in mice. ITGß3-knockout (KO) mice showed normal conditioned fear responses that were similar to those of control wild-type mice. However, anxiety-like behaviour appeared substantially compromised and could be reversed to control levels by lentivirus-mediated re-expression of ITGß3 bilaterally in the ventral hippocampus. In hippocampal slices, the loss of ITGß3 activity did not compromise hebbian forms of plasticity--neither acute pharmacological disruption of ITGß3 ligand interactions nor genetic deletion of ITGß3 altered long-term potentiation (LTP) or long-term depression (LTD). Moreover, we did not detect any changes in short-term synaptic plasticity upon loss of ITGß3 activity. In contrast, acutely disrupting ITGß1-ligand interactions or genetic deletion of ITGß1 selectively interfered with LTP stabilisation whereas LTD remained unaltered. These findings indicate a lack of requirement for ITGß3 in the two robust forms of hippocampal long-term synaptic plasticity, LTP and LTD, and suggest differential roles for ITGß1 and ITGß3 in supporting hippocampal circuit functions.
Subject(s)
Fear/physiology , Hippocampus/physiology , Integrin beta3/genetics , Long-Term Potentiation/genetics , Animals , Excitatory Postsynaptic Potentials , Integrin beta1/genetics , Integrin beta1/physiology , Integrin beta3/physiology , Long-Term Potentiation/physiology , Long-Term Synaptic Depression/genetics , Long-Term Synaptic Depression/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, AMPA/physiologyABSTRACT
Evidence has accumulated that point to the tissue plasminogen activator (tPA), a serine protease historically associated with blood physiology, as an important regulator of the central nervous system functioning. tPA is highly expressed in the limbic system where it regulates neuronal viability and experience-induced plasticity. In the amygdala tPA is a critical mediator of stress-induced structural and functional rearrangements that ultimately shape up behavioral responses to stressful stimuli. The importance of tPA in the limbic system was confirmed using tPA-deficient mice; these animals do not show biochemical, structural and behavioral signatures normally associated with stress. tPA-mediated facilitation of experience-induced plasticity in the limbic system is mediated by a complex mechanism that may involve direct or indirect interactions of tPA with NMDA receptor, its binding to the LRP receptor or activation of brain-derived growth factor.