Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.

The amygdala is under inhibitory control from the cortex through the activation of local GABAergic interneurons. This inhibition is greatly diminished during heightened emotional states due to dopamine release. However, dopamine excites most amygdala interneurons, suggesting that this dopaminergic gate may be mediated by an unknown subpopulation of interneurons. We hypothesized that this gate is mediated by paracapsular intercalated cells, a subset of interneurons that are innervated by both cortical and mesolimbic dopaminergic afferents. Using transgenic mice that express GFP in GABAergic interneurons, we show that paracapsular cells form a network surrounding the basolateral complex of the amygdala. We found that they provide feedforward inhibition into the basolateral and the central amygdala. Dopamine hyperpolarized paracapsular cells through D1 receptors and substantially suppressed their excitability, resulting in a disinhibition of the basolateral and central nuclei. Suppression of the paracapsular system by dopamine provides a compelling neural mechanism for the increased affective behavior observed during stress or other hyperdopaminergic states.

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The physiological significance of the large diversity of GABA A receptors is poorly understood. Using mice, which carry a point mutation that renders specific subtypes of GABA A receptors diazepam insensitive, it was recently discovered that particular types of GABA A receptors are involved in specific, behaviorally relevant signaling pathways. We have used these mice to study inhibitory synaptic transmission in the amygdala. GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) per se were not affected by the point mutations. Their modulation by diazepam, however, was altered depending on the genotype of the mice studied. Based on the different responses to diazepam, we found that IPSCs in the lateral/basolateral amygdala were mediated by both alpha2- and alpha1-subunit-containing GABA A receptors whereas those in the central amygdala were mediated only by alpha2-subunit-containing GABA A receptors. Immunohistochemical staining corroborated these findings at a morphological level. To investigate a possible link between interneuron and receptor diversity, we selectively depressed release from the subset of GABAergic terminals carrying type 1 cannabinoid receptors. These receptors are known to modulate amygdala-mediated behavior. Application of a type 1 cannabinoid receptor agonist resulted in a selective reduction of inhibitory current mediated by alpha1-subunit-containing GABA A receptors. Mice with specific diazepam-insensitive GABA A receptor subtypes therefore provide a novel tool to investigate GABA A receptor distribution and the organization of inhibitory circuits at a functional level. The crucial role of the amygdala for the mediation of anxiety is in agreement with the part that alpha2-subunit-containing GABA A receptors play in anxiolysis and their important function in this area of the brain.