Inhibition is critical for the proper functioning of neural circuits. Activity from soma- targeting inhibitory interneurons can constrain the temporal detection of inputs, synchronize the activity of large populations of cells, and balance excitatory drive to prevent uncontrolled activity. The effect of activity from dendrite-targeting inhibitory interneurons, however, is much less clear. Although modeling studies suggest that they can shape local processing of excitatory inputs, there is little to no experimental evidence to support these findings. It is the goal of this study to investigate how dendritic inhibition affects dendritic integration. The prefrontal cortex (PFC) is a region of the brain that has been implicated in higher-level cognitive processing, such as working memory. By connecting to diverse regions of the brain, the PFC is able to regulate autonomic output, motor output, and signal emotional and value significance. The importance of inhibition in PFC functioning is highlighted by the findings of abnormalities in inhibitory interneurons in the PFC of patients with schizophrenia. Schizophrenia is a neuropsychiatric disease that causes impaired working memory, a PFC-dependent cognitive process. Our study will help understand how inhibition contributes to normal PFC functioning and lay the foundation for studying how aberrant inhibition in PFC leads to the pathogenesis of schizophrenia. First, we will examine the impact of GABAB receptors on dendritic excitability and synaptic transmission. We will use two-photon microscopy, whole-cell recordings, and selective pharmacology to identify the types of channels and receptors that are located in the spines and dendrites of layer 2/3 pyramidal neurons. Then, we will examine the effect of GABAB on the calcium signals produced by these channels and receptors. We will then identify the types of channels or receptors that GABAB modulates in spines and dendrites. Finally, we will examine the impact of GABAB receptors on dendritic integration. We will use glutamate uncaging to investigate the dendritic and somatic response to single inputs and pairs of inputs. Then, we will examine how GABAB modulates the somatic and dendritic responses to these different patterns of excitatory activity. Public health relevance: Inhibition in the brain allows neural circuits to operate without losing control of activity patterns. Diseases of the brain emerge when inhibition is perturbed such that it is improperly regulated or attenuated. Our study will shed light on the process of inhibition in an area of the brain that is known to be critical for higher-level functioning and will help us understand why impaired inhibition can cause debilitating diseases such as epilepsy and schizophrenia.
Inhibition in the brain allows neural circuits to operate without losing control of activity patterns. Diseases of the brain emerge when inhibition is perturbed such that it is improperly regulated or attenuated. Our study will shed light on the process of inhibition in an area of the brain that is known to be critical for higher-level functioning and will help us understand why impaired inhibition can cause debilitating diseases such as epilepsy and schizophrenia.
| Chalifoux, Jason R; Carter, Adam G (2011) Glutamate spillover promotes the generation of NMDA spikes. J Neurosci 31:16435-46 |
| Chalifoux, Jason R; Carter, Adam G (2011) GABAB receptor modulation of synaptic function. Curr Opin Neurobiol 21:339-44 |
| Chalifoux, Jason R; Carter, Adam G (2011) GABAB receptor modulation of voltage-sensitive calcium channels in spines and dendrites. J Neurosci 31:4221-32 |
