The Stable Brain

The brain is astonishing in its complexity and capacity for change.  This has fascinated scientists for more than a century. But, a paradigm shift is underway. The plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. Without the existence of potent mechanisms that stabilize neural function, our capacity to learn and remember would be lost in the chaos of daily experiential change. This underscores two great mysteries in neuroscience: 

1. How are the functional properties of individual nerve cells and neural circuits stably maintained throughout life? 

2. In the face of potent stabilizing mechanisms, how can neural circuitry be modified during neural development, learning and memory?  

We are seeking cellular and molecular answers to these fundamental questions. Our progress promises to open new avenues for the treatment of neurological diseases that are characterized by neuronal malfunction including epilepsy, autism, post-traumatic stress disorder and psychosis.   

 

OPPORTUNITY

We are actively seeking applications for postdoctoral fellows to join our research team. If interested, please contact Graeme Davis directly, contact information on this site.  

 

Introduction to Neuronal Homeostatic Control

 

Homeostasis is defined as the ability of a cell or system of cells to detect a perturbation and, in the continued presence of that perturbation, generate a compensatory response that precisely restores baseline function. Evolutionarily conserved homeostatic signaling systems stabilize the function of individual neurons and neural circuitry in organisms that range from insects to human. Our goal is to delineate these homeostatic signaling systems in cellular and molecular detail and define how they succeed or fail in health and disease. 

TOP: Each neuronal cell type has cell type-specific firing properties that are determined by the balance of excitatory and inhibitory synaptic inputs as well as the ion channels that the neuron expresses (red and blue ovals). In response to a perturbation (arrow) a neuron can adjust synaptic drive and ion channel expression to re-establish normal baseline firing properties. This is the definition of homeostatic control of neural function. 

BOTTOM: Neurotransmission is controlled by homeostatic signaling. At the neuromuscular junction (shown), the release of synaptic vesicles depolarized the postsynaptic cell. In response to impaired postsynaptic neurotransmitter receptor sensitivity, a homeostatic signaling system causes more vesicles to be released. This effect precisely offsets the magnitude of the postsynaptic perturbation. This effect can be induced in seconds to minutes and can be sustained for the life of an organism. This form of homeostatic control is evolutionarily conserved from fly to human, implying an ancient and fundamental role in stabilizing the synaptic communication of information throughout the nervous system. 

 

Mechanisms of Presynaptic Homeostatic Plasticity

 

We used the powerful forward genetics of Drosophila to screen genes that, when mutated, block presynaptic homeostatic plasticity. All of our screens have been based on direct, electrophysiological measurement of synaptic transmission, entailing more than 12,000 intracellular recordings and, recently, coverage of the nearly 50% of the entire Drosophila genome. We are converging upon a set of essential signaling systems, diagrammed below. Many of the molecular mechanisms that we have identified are completely novel within the nervous system, highlighting the importance of unbiased gene screening as a path to discovery. Recent mechanisms include: 1) ENaC channel trafficking to the presynaptic membrane (Younger et al., 2013), 2) a novel intercellular signal achieved by Endostatin (Wang et al., 2014) and 3) the action of an innate immune receptor never before studied in the nervous system of any organism (Harris et al., 2015). Future efforts will include translation to mammalian systems and models of neurological and psychiatric disease.  In addition, we will pursue systems biology approaches to understand how recently identified signaling systems are integrated to achieve the coherent, robust homeostatic control of synaptic transmission. 

 

 

Diagram of a synapse. The presynaptic release site is centered upon the presynaptic calcium channel (Cav2). Neurotransmitter vesicles are released opposite to postsynaptic glutamate receptors (GluR). We have defined three major signaling systems that converge to achieve the homeostatic control of synaptic vesicle release, each defined by a brown, blue or orange oval. These mechanisms include the regulated insertion of ENaC channels (brown), release of signaling factors from the extracellular matrix (blue) and activation of innate immune signaling (orange). 

Homeostatic Design

 

Homeostatic signaling systems must be tailored to the unique properties of each cell type in the brain. In general, homeostatic signaling systems are based on feedback control, an outline of which is diagrammed below. This simple diagram serves to highlight the many questions that remain unanswered despite our recent progress. Ultimately, homeostatic signaling in the brain is likely to involve many interconnected systems such as this, inclusive of not only feedback but also feedforward signaling, and the incorporation of many reversible and irreversible enzymatic reactions. 

 
Homeostatic signaling systems are built upon feedback control. A simplistic signaling system is diagrammed to illustrate how much remains to be learned. Baseline neural function is detected by a sensor. The information from the sensor is compared to the cell set point, which is genomically defined. If the sensor and set point differ, an error signal is produced, integrated over time and fed back into the system as negative feedback. If the error is offset to zero, perfect homeostasis is achieved. We do not know the nature of a true sensor for neural activity, nor do we know how this information is communicated to a genomically defined set point. Therefore, the chemical identity of the error signal and the nature of signal integration remain unknown. Ultimately, cellular and molecular mechanisms must be able to explain the concepts defined in red. Recent work has highlighted the first mechanisms responsible for the bi-directional control of neurotransmission (Gavino et al., 2015).  Additional work has defined mechanisms for the analogue control of presynaptic release (Younger et al., 2013). We have begun to define the intercellular signaling systems that achieve homeostatic communication between cells in the nervous system (Wang et al., 2014; Harris et al., 2015). 

Homeostatic signaling systems are built upon feedback control. A simplistic signaling system is diagrammed to illustrate how much remains to be learned. Baseline neural function is detected by a sensor. The information from the sensor is compared to the cell set point, which is genomically defined. If the sensor and set point differ, an error signal is produced, integrated over time and fed back into the system as negative feedback. If the error is offset to zero, perfect homeostasis is achieved. We do not know the nature of a true sensor for neural activity, nor do we know how this information is communicated to a genomically defined set point. Therefore, the chemical identity of the error signal and the nature of signal integration remain unknown. Ultimately, cellular and molecular mechanisms must be able to explain the concepts defined in red. Recent work has highlighted the first mechanisms responsible for the bi-directional control of neurotransmission (Gavino et al., 2015).  Additional work has defined mechanisms for the analogue control of presynaptic release (Younger et al., 2013). We have begun to define the intercellular signaling systems that achieve homeostatic communication between cells in the nervous system (Wang et al., 2014; Harris et al., 2015). 

 

Homeostatic Plasticity and the Mechanisms of Disease

If homeostatic signaling is impaired, the nervous system will be 

less robust to perturbations including genetic, immunological or 

environmental stress. We are actively exploring the intersection of homeostatic signaling with the genetics of both autism and neurodegenerative disease. We are translating our mechanistic advances to search for novel, disease modifying strategies using mice and other models of disease. The broad clinical expertise at UCSF provides an ideal environment for collaboration. 

Anatomical illustration by Leonardo da Vinci