Austin R. Graves, Ph.D. - US grants

DESCRIPTION (provided by applicant): Though intrinsic plasticity is an important mechanism by which the brain may encode and store information, it has been largely understudied in the learning and memory field. Our lab recently described a novel form of intrinisic plasticity in the excitability of pyramidal neurons in subiculum, the primary output pathway of the hippocampus. Plasticity of burst firing followed theta-patterned synaptic stimulation and did not depend on AMPA or NMDA receptors, but rather on synergistic activation of metabotropic muscarinic and glutamate receptors (mAChRs and mGluRs). By activating different sub-types of metabotropic receptors during dendritic stimulation, a long lasting enhancement or suppression of burst firing was induced (Moore et al., Neuron 2009). While this mechanism may exert profound influence of the fidelity of information transfer from the hippocampus, the mechanisms underlying burst plasticity expression remain unknown. We are now studying whether burst plasticity occurs in CA1 neurons. Using whole-cell current-clamp and cell-attached voltage- clamp recordings, we found that while burst plasticity can be induced in these neurons, the pharmacology of burst plasticity differed between CA1 and subiculum. In burst-firing subicular neurons, synergistic activation of mGluR1 and mAChRs was required to induce a long lasting increase in burst firing, whereas mGluR5 mediated a suppression of burst firing. In regular-spiking CA1 neurons, however, preliminary data suggest that mGluR5 mediated enhanced burst firing and antagonism of mGluR1 and mAChRs did not block the induction of increased burst firing. In addition to elucidating the pharmacological processes contributing to burst plasticity induction, I will also explore how plasticity is expressed in CA1. Is increased burst firing achieved by upregulating a depolarizing conductance, such as a voltage-gated sodium or calcium channel, by downregulating a potassium channel, or a combination of both? Using selective blockers for numerous voltage- gated and calcium-activated channels, I will record specific ionic currents following burst plasticity induction to determine the molecular identity of plasticity expression. Further scrutiny of the mechanisms underlying burst plasticity will yield valuable insight regarding the role of intrinsic plasticity in modulating hippocampal integration and output, and may further suggest novel mechanisms for information storage. PUBLIC HEALTH RELEVANCE: This project studies the cellular underpinnings of a novel form of information storage in the hippocampus, a crucial brain area involved in memory formation. Presently, very little is known regarding the molecular mechanisms linking changes in neuronal signaling to memory. Elucidating these mechanisms will increase our understanding of the complex processes behind memory and may yield valuable insights into pathological conditions associated with memory deficits, such as Alzheimer's and dementia.

The synapse is the fundamental unit of the nervous system, enabling communication between brain cells and providing a substrate for experience-dependent plasticity to drive adaptive behaviors. Altering the strength of synapses between specific cells or neuronal ensembles is thought to underlie higher brain functions such as learning and memory, whereas synaptic degradation is observed in many neurological pathologies, such as Alzheimer's disease (AD) and related dementias. Despite the clear significance of synaptic communication, the relationship between impaired synaptic function, progression of AD symptoms, and cognitive decline remains unclear. However, recent breakthroughs in molecular microscopy enable direct imaging of the progression of pathological synaptic deficits in mouse models of Alzheimer's disease. Our approach is to fluorescently tag synaptic proteins and AD markers to track them throughout disease progression using in vivo two-photon microscopy. By imaging large populations of synapses comprising entire cortical and hippocampal circuits, we strive to gain a detailed understanding of how molecular pathologies affect synaptic physiology and ultimately give rise to cognitive decline. This approach will yield a detailed time course of the progression of synaptic and cognitive Alzheimer's pathologies that may reveal effective treatment windows and novel avenues for therapeutic interventions for human disease.