The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neuropsychiatric diseases, including schizophrenia and depression. Pyramidal neurons are the principal cells of the prefrontal cortex, and process diverse excitatory and inhibitory synaptic inputs. These neurons also receive extensive dopaminergic inputs from subcortical regions that modulate intrinsic and synaptic physiology. Dopamine activates metabotropic D1 receptors to enhance pyramidal neuron firing and support cognitive functions like working memory. However, previous studies have found heterogeneous effects of D1 receptors on excitatory and inhibitory responses at pyramidal neurons. We recently discovered that D1 receptors are selectively expressed in only a subpopulation of layer 5 pyramidal neurons (D1+ neurons). These neurons have compact dendrites, high input resistance, minimal h-current and pronounced burst firing compared to their D1- neighbors. Importantly, they are also selectively modulated by D1 receptors, which signal through the protein kinase A (PKA) pathway to boost excitability. The goal of this proposal is to assess how D1 receptors modulate excitatory and inhibitory responses at D1+ neurons in the mouse PFC. We first characterize the different excitatory inputs onto D1+ neurons, using a powerful combination of whole-cell recordings, optogenetics and two-photon microscopy. We then use these approaches to assess the properties of inhibitory inputs onto D1+ neurons, which derive from a variety of GABAergic interneurons. In both cases, we examine the mechanisms that underlie differential synaptic responses at D1+ neurons and their D1-neighbors. Having defined these connections, we test our hypothesis that D1 receptors regulate excitatory and inhibitory synapses only at D1+ neurons. The proposed experiments will reveal how this subpopulation of pyramidal neurons interacts with their long-range and local circuits. The results from these experiments will answer fundamental questions about dopamine regulation of cellular and synaptic physiology. They will also help to identify novel therapeutic targets for the many neuropsychiatric diseases that arise from disrupted dopamine modulation in the PFC.

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Our goal is to determine how metabotropic D1 receptors modulate synaptic responses at pyramidal neurons in the mouse prefrontal cortex. We will first characterize how diverse excitatory and inhibitory inputs form connections onto a subpopulation of D1-expressing pyramidal neurons. We will then establish the mechanisms by which D1 receptors selectively regulate excitatory and inhibitory responses at these D1+ neurons.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Nadler, Laurie S
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New York University
Schools of Arts and Sciences
New York
United States
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Liu, Xingchen; Carter, Adam G (2018) Ventral Hippocampal Inputs Preferentially Drive Corticocortical Neurons in the Infralimbic Prefrontal Cortex. J Neurosci 38:7351-7363
Anastasiades, Paul G; Marlin, Joseph J; Carter, Adam G (2018) Cell-Type Specificity of Callosally Evoked Excitation and Feedforward Inhibition in the Prefrontal Cortex. Cell Rep 22:679-692
McGarry, Laura M; Carter, Adam G (2017) Prefrontal Cortex Drives Distinct Projection Neurons in the Basolateral Amygdala. Cell Rep 21:1426-1433
McGarry, Laura M; Carter, Adam G (2016) Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex. J Neurosci 36:9391-406
Seong, Hannah J; Behnia, Rudy; Carter, Adam G (2014) Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex. J Neurophysiol 111:1960-72
Marlin, Joseph J; Carter, Adam G (2014) GABA-A receptor inhibition of local calcium signaling in spines and dendrites. J Neurosci 34:15898-911
Little, Justin P; Carter, Adam G (2013) Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. J Neurosci 33:15333-42
Seong, Hannah J; Carter, Adam G (2012) D1 receptor modulation of action potential firing in a subpopulation of layer 5 pyramidal neurons in the prefrontal cortex. J Neurosci 32:10516-21
Little, Justin P; Carter, Adam G (2012) Subcellular synaptic connectivity of layer 2 pyramidal neurons in the medial prefrontal cortex. J Neurosci 32:12808-19
Chalifoux, Jason R; Carter, Adam G (2011) Glutamate spillover promotes the generation of NMDA spikes. J Neurosci 31:16435-46

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