A revolution in psychiatric genetics has led to a growing list of candidate genes conveying susceptibility to autism spectrum disorders (ASD). The implicated molecules have diverse functions, ranging from protein synthesis control to synaptic adhesion, leading to the hypothesis that these disparate genetic changes converge onto a common neuronal circuit pathology in ASD rather than a common molecular pathology. We have developed methods for circuit mapping that enable measurements of functional synaptic connectivity with single-neuron resolution. By expanding a two-photon beam in the imaging plane using the temporal focusing method, and restricting channelrhodopsin to the soma and proximal dendrites, we are able to reliably evoke action potentials in individual neurons, verify spike generation with GCaMP6s, and determine the presence or absence of synaptic connections with patch-clamp electrophysiological recording. We are searching for common circuitry endophenotypes among multiple animal models of ASD using this method.

Endocannabinoids are powerful neuromodulators that regulate learning, motivation, decision making, and emotion. Whereas endocannabinoids are released with spatial and temporal precision in response to environmental stimuli to control learning and emotional responses, the THC in marijuana hijacks the cannabinoid system. Given that there is evidence that the endocannabinoid system may be off balance in anxiety disorders, PTSD and schizophrenia, it is important to understand how marijuana affects the development and function of brain circuits involved in emotional regulation in models of genetic and environmental susceptibility to these disorders. We combine a constitutive or cell class-specific knock out model of a candidate schizophrenia susceptibility gene with adolescent exposure to cannabinoids and determine how synaptic connectivity, behavior and neural activity during behavior is altered.

The amygdala is a critical plasticity site for the acquisition of emotionally charged memories and plays a significant role in emotional behavior. Alterations in amygdala function are consistent with anxiety and social motivation deficits in both disorders, and paranoid ideations in schizophrenia. The lateral amygdala (LA) is the primary site of synaptic plasticity in fear learning. It receives sensory information from both the thalamus and cortex such that it can associate intrinsically aversive stimuli with neutral stimuli that are paired with it. The basal amygdala (BA) is a central integrator of emotional context. The BA is driven by the LA and regulated by inputs from the medial prefrontal cortex (mPFC) to provide executive control over fear behavior. Amygdala processing is regulated by several classes of inhibitory neurons either local circuit interneurons or those located in specialized clusters like the intercalated cells surrounding the basolateral amygdala (BLA). From the BLA information travels to the central amygdala which is the major output nuclei for fear expression. Understanding how individual elements within the amygdala processing stream are altered in models of autism and schizophrenia is the goal of this project.