Psychostimulants, such as methamphetamine and cocaine, are highly addictive, and abused by millions of people. Recent work from our laboratory has established that drug exposure reduces slow inhibition, mediated by GABA(B) receptors that activate GIRK channels. We have delineated two different mechanisms of drug-dependent plasticity in VTA neurons. In GABA neurons, psychostimulant-dependent depression of GABA(B)-GIRK currents involves de-phosphorylation of the GABA(B) R2 receptor via the protein phosphatase PP2a. In DA neurons, psychostimulant-dependent depression of GABA(B)-GIRK currents involves the GIRK3 subunit and an endosomal trafficking protein SNX27. We are currently examining the role of GIRK channels in projection specific VTA neurons using chemogenetics (i.e. DREADDs), and searching for new GIRK regulatory proteins using BioID. To develop new therapeutics for treating addiction, it is essential to elucidate the components of drug-dependent plasticity in the brain and discover novel protein targets in the reward pathway.

For topical review, see Rifkin et al (2017) Trends in Pharmacological Sciences

As part of the NIH Brain Initiative, our lab is actively involved in developing new innovative neurotechniques for optically dissecting the function of neuromodulators in the brain of awake animals.  We have created cell-based biosensors (CNiFERs) to optically measure the release of neuropeptides in cell-specific and circuit-specific processes in the brain, in collaboration with the Kleinfeld laboratory at the Univ. of California, San Diego. CNiFERs detect nM concentrations of transmitter, have a temporal resolution of seconds, and a spatial resolution of < 100 μm. In collaboration with Qin laboratory at the Univ. of Texas at Dallas, we are developing a technique of photo-releasing peptides and other modulators in the brain with two photon precision.  In combination with CNiFERs, we can begin to understand the diffusion of peptides in the brain.

For topical papers, see Muller et al (2014) Nature Methods &  Xiong et al (2020) Angew Chem Int Ed

Excessive alcohol use is one of the top 10 contributors to disability worldwide, and an estimated 16 million Americans meet the criteria for alcohol use disorders (AUD). AUD is heritable (50-60%), polygenic and results from the contributions of genes and environment. We are part of a multi-institution research program, called the Collaborative Studies on the Genetics of Alcoholism (COGA), supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA).  COGA’s primary goal is to identify the genes that increase or decrease the risk of alcoholism. Our laboratory is using human induced pluripotent stem cell (hiPSC)-based models to study the effect of risk genes on the functional activity of human neurons, to better understand the role of genetics in AUD.

For topical review, see Prytkova et al (2018) Alcohol Clin Exp Res.

Schizophrenia, bipolar disorder and autism are common and debilitating neurodevelopmental disorders that together affect more than 5 million Americans. Despite more than fifty years of research, no cures exist, and the standard of treatment remains unsatisfactory. Heterozygous mutations of neurexin-1 (NRXN1) have been repeatedly associated with schizophrenia (SZ) and autism spectrum disorder (ASD). In collaboration with Dr. Brennand, we are investigating how NRXN1+/- deletions perturb the NRXN1 isoform repertoire and impact neuronal maturation and synaptic function, using experimental manipulations of control and NRXN1+/- patient-derived excitatory and inhibitory neurons.

For topical review, see Fernando et al (2020) Nat Genet.