Theories stipulate that memories are encoded within networks of cortical projection neurons (PNs). Conversely, GABAergic interneurons (INs) are thought to function primarily to inhibit PNs and thereby impose network gain control, an important but purely modulatory role. Here we show in male mice that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex (mPFC) somatostatin interneurons (SST-INs), and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST-and parvalbumin (PV)-INs provides a potential circuit basis for SST-INevoked disinhibition of mPFC output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that rather than constrain mnemonic processing, potentiation of SST-IN activity represents an important causal mechanism for conditioned fear.

A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network.

Results from single-molecule and macroscopic electrophysiology and kinetic analysis provide a model for activation of the glutamate-bound NMDA receptor by glycine.