Research Associate,
Biology Department
Rm1217 Bioscience Research Bldg., 
University of Maryland
4066 Campus Drive
College Park, 
MD 20742
email: smurase@umd.edu
Tel: 301-405-7222                   

    I work to understand mechanisms responsible for the life and death of neurons. I have particularly focused on developmental neuronal death, a normal process that occurs throughout the nervous system within a specific, brief period. Since this process ultimately eliminates as many as half of all neurons that are generated, it plays an important role for determining the structure and function of the mature brain. I wish to understand this process on multiple levels, so I use a wide range of techniques: molecular, genetic, cellular, anatomical, electrophysiological, optical imaging, and behavioral.

    Recently, working with Dr. Ron McKay, I found that being in spontaneously active networks is essential for survival of neonatal neurons, and that this activity is promoted by neurotrophin (Murase et al. J. Neurosci. 2011). In these young neurons, the neurotransmitter GABA (which is excitatory at this developmental stage) plays a critical role in inducing calcium influx through L-type channels.  This calcium influx works together with integrin and activates Akt, a Ser/Thr kinase that is known to support cell survival. This study implies that developmental neuronal death has the effect of sparing only neurons that are successfully linked to active networks with strong GABAergic inputs, thus ensuring that surviving circuits have an appropriate proportion of inhibitory input.   

    What then occurs downstream of Akt signaling to allow young neurons to survive? I found the expression level of the tumor suppressor, p53 is regulated by this pathway (Murase et al. Eur. J. Neurosci. 2011). Genetic deletion of p53 reduced the amount of neuronal death without affecting the onset or the duration of the death period. In p53 knockout mice, more neurons survived the death period, some with somata of normal size, but some with abnormally small somata. Survival signaling components were significantly less abundant in the small neurons. This study showed that p53 is the key downstream regulator of the novel survival pathway to determine the number of neurons in postnatal life.

    I further found that integrin, a cell-adhesion molecule, is important for the survival of neurons in neonates. Is this signal stable or changing over the period of developmental death? I found that laminin, the substrate for integrin, was up-regulated during the death period. This up-regulation was achieved by the down-regulation of Matrix-metalloproteinase-9 (MMP-9), which cleaves (and thus inactivates) laminin (Murase and McKay J. Biol. Chem. 2012 ). Inhibition of MMP-9 activity reduced neuronal death, showing that integrin signaling plays an active rather than merely a permissive role in neurotrophin-network activity-induced survival signaling.     

     In many neurological disorders such as epilepsy, schizophrenia and autism, the balance of neural excitation and inhibition (E/I balance) is altered. In many pathological conditions neurons are chronically over-activated. Although neurons can detect their input levels and adjust their excitability in order to maintain an appropriate range of spiking activity, little was known of the influence these mechanisms exert on survival signaling. I reported that chronic elevation of activity causes, in mature neurons, a loss of signal transducer and activator of transcription 3 (STAT3) signaling and a return to neurotrophin dependency for survival, a characteristic feature of neonatal neurons during the death period (Murase et al. J. Neurosci. 2012).  These results suggest STAT3 regulates a state transition between neonatal and adult survival signaling mechanisms. Recently, I found that this transition is regulated by calcineurin-dependent ubiquitination and proteasomal degradation of STAT3 (Murase J. Biol. Chem. 2013).

    For integrated summary of my work, please see my latest review (Murase Mol. Neurobiol. 2014).


Subpages (2): CV publications