Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex.

Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels.

D1 receptor modulation of action potential firing in a subpopulation of layer 5 pyramidal neurons in the prefrontal cortex.

Dopamine modulation in the prefrontal cortex is important for cognitive processing and disrupted in diverse neuropsychiatric diseases. Activation of D1 receptors is thought to enable working memory by enhancing the firing properties of pyramidal neurons. However, these receptors are only sparsely expressed in the prefrontal cortex, and how they impact individual neurons remains unknown. Here we study D1 receptor modulation of layer 5 pyramidal neurons in acute slices of the mouse prefrontal cortex. Using whole-cell recordings and two-photon microscopy, we show that neurons expressing D1 receptors have unique morphological and physiological properties. We then demonstrate that activation of these receptors selectively enhances the firing of these neurons by signaling via the protein kinase A pathway. This finding of robust D1 receptor modulation in only a subpopulation of neurons has important implications for cognitive function and disease.