Glutamate is the major fast excitatory neurotransmitter in most regions of the central nervous system (CNS), including the hypothalamus. A decreased level of glutamate activity can be found during the use of antiglutamate receptor drugs (including some drugs of abuse), selective degeneration of glutamatergic neurons or projections, and embryonic development. Observations from other laboratories revealed increased cholinergic functions in the CNS during each of these three conditions. Our recent experiments in hypothalamic neuronal cultures indicated that a chronic blockade of ionotropic glutamate receptors dramatically increases excitatory acetylcholine (ACh) synaptic activity and the number of cholinergic neurons. Data suggested that during a long-term decrease in glutamate transmission in the hypothalamus in vitro, ACh, which normally exhibits only weak activity in the hypothalamus, plays the role of the major excitatory neurotransmitter and supports the excitation/inhibition balance. We also hypothesized that an increase in excitatory ACh transmission represents a novel form of neuronal plasticity that regulates the activity and excitability in neurons during a decrease in glutamate excitation. However, the mechanisms of glutamate-dependent regulation of ACh transmission in the CNS have not been studied. They will be studied in the proposed research in hypothalamic neurons. First, using rat hypothalamic cultures, we will test the hypothesis that during decrease in glutamate transmission ACh and glutamate are co-released from the same synaptic terminals. Second, using hypothalamic cultures, we will test the hypothesis that the induction of cholinergic phenotype in neurons is regulated through a CREB-dependent signal transduction pathway. Third, we will test the prediction that a chronic blockade of glutamate NMDA receptors in rats in vivo increases cholinergic phenotypic properties in hypothalamic neurons. This will be studied using electrophysiology, Ca 2+ imaging, immunostaining, and molecular biology. This project addresses the fundamental mechanisms of neuronal plasticity and regulation of neuronal activity that can take place in neuronal circuits during a decrease in glutamate excitation. Data obtained here may have an important clinical relevance, given that glutamate receptor antagonists are used for chronic treatment of patients, and some glutamate receptor antagonists are drugs of abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Schools of Medicine
Kansas City
United States
Zip Code
Hascup, Kevin N; Bao, Xiaodong; Hascup, Erin R et al. (2011) Differential levels of glutamate dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 mice and the effects of overexpression of the Glud1 gene on glutamate release in striatum. ASN Neuro 3:
Park, Won-Mee; Wang, Yongfu; Park, Soodong et al. (2011) Interplay of chemical neurotransmitters regulates developmental increase in electrical synapses. J Neurosci 31:5909-20
Michaelis, E K; Wang, X; Pal, R et al. (2011) Neuronal Glud1 (glutamate dehydrogenase 1) over-expressing mice: increased glutamate formation and synaptic release, loss of synaptic activity, and adaptive changes in genomic expression. Neurochem Int 59:473-81
Wang, Yongfu; Denisova, Janna V; Kang, Ki Sung et al. (2010) Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke. J Neurophysiol 104:3551-6
Bao, Xiaodong; Pal, Ranu; Hascup, Kevin N et al. (2009) Transgenic expression of Glud1 (glutamate dehydrogenase 1) in neurons: in vivo model of enhanced glutamate release, altered synaptic plasticity, and selective neuronal vulnerability. J Neurosci 29:13929-44
Leininger, Eric; Belousov, Andrei B (2009) Recovery of network-driven glutamatergic activity in rat hippocampal neurons during chronic glutamate receptor blockade. Brain Res 1251:87-102
Liu, Xinhuai; Popescu, Ion R; Denisova, Janna V et al. (2008) Regulation of cholinergic phenotype in developing neurons. J Neurophysiol 99:2443-55
Arumugam, Harsha; Denisova, Janna V; Neve, Rachael L et al. (2008) Use of calcium imaging for analysis of neuronal gap junction coupling. Neurosci Lett 445:26-30
de Rivero Vaccari, Juan Carlos; Corriveau, Roderick A; Belousov, Andrei B (2007) Gap junctions are required for NMDA receptor dependent cell death in developing neurons. J Neurophysiol 98:2878-86
Leininger, Eric; Belousov, Andrei B (2006) Homeostatic plasticity: comparing and contrasting cortical and hippocampal studies. A review. Crit Rev Neurobiol 18:125-34

Showing the most recent 10 out of 11 publications