Stephen Rayport, MD, PhD
Animal Models of Psychiatric Disease, Synapses and Circuits
Dysregulated glutamatergic neurotransmission has been strongly implicated in schizophrenia. Similarly, alterations in glutamatergic neurotransmission as a result of repeated stimulant administration have been strongly implicated in addiction. Recent studies have highlighted the therapeutic promise of modulating glutamatergic transmission in both disorders. We have shown that neurons from glutaminase (GLS1) knockout mice show an activity-dependent presynaptic reduction in glutamatergic synaptic transmission, suggesting that inhibition of glutaminase may have therapeutic potential. While GLS1 knockout mice die shortly after birth, GLS1 haploinsufficient mice with one functional GLS1 allele (GLS1 hets) are remarkably normal. Strikingly, functional imaging reveals that the mice have focal hypometabolism in the hippocampus, mainly involving the CA1 subregion, which is the exact inverse of recent imaging findings in patients with schizophrenia. GLS1 het mice are less responsive to the behavioral and neurochemical effects of stimulants. Thus GLS1 het mice manifest phenotypes consistent with resilience to schizophrenia and addiction. We are now seeking to identify the crucial glutamatergic circuits using a conditional transgenic approach combined with optogenetics to measure functional connectivity in the same circuits. One of the crucial glutamatergic circuits appears to be the midbrain dopamine neurons themselves. These neurons are thought to mediate the rewarding effects of abused drugs, as well as to figure prominently in the pathophysiology of schizophrenia. We have shown in a coordinated series of molecular, physiological and morphological studies that the neurons use glutamate as a co-transmitter. Mice with a conditional knockout of glutamate show an attenuated response to stimulants indicating that dopamine neuron glutamate cotransmission may be important in addictive processes. In quasi-horizontal brain slices that encompass the neurons and their limbic projections, we have shown that when dopamine neurons fire, dopamine neuron glutamate transmission shows facilitation at higher, burst-firing frequencies, as a result of concomitant dopamine release. Counterbalanced pre- and postsynaptic actions determine the frequency dependence of dopamine modulation; at lower firing frequencies dopamine modulation is not apparent, while at burst firing frequency postsynaptic facilitation dominates and dopamine becomes facilitatory. Dopamine neurons thus convey a fast glutamatergic signal that is accentuated at burst firing frequencies by concomitant dopamine release. This unique signal may play an important role in encoding salience during reward learning, and may be an important substrate for enduring physiological and pathological changes in dopamine system function. Taken together, the hope is that by countering psychostimulant-induced neuroplastic changes we may find new ways to treat schizophrenia and addiction.
Biology of Neurologic and Psychaitric Disorders (G4100)
Functional connectome analysis of amphetamine action at dopamine neuron synapses (RFMH, Prime/CU, Subcontract)
Project Date: 05/01/2015-02/29/2020
Mapping dopamine neuron cotransmission by proximity detection (CU, Prime/RFMH, Subcontract)
Project Date: 08/01/2015 - 07/31/2017
- Nao Chuhma, MD PhD, Research Scientist
- Susana Mingote, PhD, Research Scientist
- Abigail Kalmbach, PhD, Postdoctoral Fellow
- Leora Yetnikoff, PhD, Postdoctoral Fellow
- Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, Ahmari SE, Moore H, Kellendonk C (2014). Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron. 81:153-164.
- Chuhma N, Mingote S, Moore H, Rayport S (2014). Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling. Neuron. 81:901-912.
- Bae N, Wang Y, Li L, Rayport S, Lubec G (2013). Network of brain protein level changes in glutaminase deficient fetal mice. J Proteomics 80:236–249.
- Mihali A, Subramani S, Kaunitz G, Rayport S, Gaisler-Salomon I (2012). Modeling resilience to schizophrenia in genetically modified mice: a novel approach to drug discovery. Expert Rev Neurother 12:785–799.
- Gaisler-Salomon I, Wang Y, Chuhma N, Zhang H, Golumbic YN, Mihali A, Arancio O, Sibille E, Rayport S (2012) Synaptic underpinnings of altered hippocampal function in glutaminase-deficient mice during maturation. Hippocampus 22:1027-1039.
- Chuhma N, Tanaka KF, Hen R, Rayport S (2011) Functional connectome of the striatal medium spiny neuron. J Neurosci 31:1183-1192 .
- Hnasko TS, Chuhma N, Zhang H, Goh GA, Sulzer D, Palmiter RD, Rayport S, Edwards RH (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643-656.
- Guo N, Guo W, Kralikova M, Jiang M, Schieren I, Narendran R, Slifstein M, Abi-Dargham A, Laruelle M, Javitch JA, Rayport S (2009) Impact of D2 receptor internalization on binding affinity of neuroimaging radiotracers. Neuropsychopharmacology ePub 2009/12/04.
- Chuhma N, Choi WY, Mingote S, Rayport S (2009) Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection. Neuroscience 164:1068-1083.
- Gaisler-Salomon I, Miller GM, Chuhma N, Lee S, Zhang H, Ghoddoussi F, Lewandowski N, Fairhurst S, Wang Y, Conjard-Duplany A, Masson J, Balsam P, Hen R, Arancio O, Galloway MP, Moore HM, Small SA, Rayport S (2009) Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia. Neuropsychopharmacology 34:2305-2322.
- Masson J, Darmon M, Conjard A, Chuhma N, Ropert N, Thoby-Brisson M, Foutz A, Parrot S, Miller GM, Jorisch R, Polan J, Hamon M, Hen R, Rayport S (2006) Mice lacking brain/kidney phosphate-activated glutaminase (GLS1) have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth. J Neurosci, 26:4660-71.
- Chuhma N, Zhang H, Masson J, Zhuang X, Sulzer D, Hen R, Rayport S (2004) Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses. J Neurosci 24:972-981.
For a complete list of publications, please visit PubMed.gov