Traumatic fear memories can be inhibited by behavioral therapy for humans, or by extinction training in rodent models, but are prone to recur. Under some conditions, however, these treatments generate a permanent effect on behavior, which suggests that emotional memory erasure has occurred. The neural basis for such disparate outcomes is unknown. We found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in the lateral amygdala. A transient up-regulation of this form of plasticity, which involves phosphorylation of the glutamate receptor 1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.Fear conditioning is the development of a fearful emotional response to a neutral cue [a conditioned stimulus (CS)] that occurs together with an unpleasant event [an unconditioned stimulus (US)]. Fear memories present as defensive reactions to the CS for a period of up to many months after learning (1). However, when conditioned subjects repeatedly encounter a CS without a reinforcing US, responses to a CS that no longer predicts harm are diminished in a process known as extinction. This paradigm is analogous to human exposure-based therapy for traumatic memories (2), in which maladaptive fear is suppressed by exposure to stimuli that were present at the time of trauma. However, because fear can recur after these treatments, extinction probably does not affect emotional memory, which can later be reactivated by specific cues (3,4).A number of studies indicate that a more lasting reduction of fear can be dependent on the conditions at the time of extinction, such as the age of the subjects (5), the intertrial spacing of stimuli (6-8), or the time elapsed since initial learning (9,10). Because even strong reminder cues do not trigger the recurrence of conditioned fear in some cases (5-8), an intriguing possibility is that, under the right conditions, permanent erasure of fear memory occurs during the course of extinction. Such techniques could be useful in the treatment of emotional disorders. However, maximizing this approach requires an understanding of the cellular and molecular mechanisms underlying this fear erasure, which at present remain obscure.

The majority of excitatory synapses in the mammalian CNS are formed on dendritic spines1, and spine morphology and distribution are critical for synaptic transmission2–6, synaptic integration and plasticity7. Here, we show that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (Npn-2) and plexinA3 (PlexA3), exhibit increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn-2−/− brain slices cortical layer V and DG GCs exhibit increased mEPSC frequency. In contrast, a distinct Sema3A–Npn-1/PlexA4 signaling cascade controls basal dendritic arborization in layer V cortical neurons but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn-2 to apical dendrites and of Npn-1 to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signaling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signaling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology.