Basic mechanisms regulating neuronal excitability and cognitive functions

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BACKGROUND: Memory decline associated with natural aging is attributed to deficient neuronal plasticity in brain circuits necessary for memory processes.             Transmission of information within brain circuits occurs via transmission of a chemical signal at synapses. This chemical signal is then translated into an electrical signal (neuronal firing) that will convey information to the next neuron, a process that is tightly controlled by neuronal intrinsic excitability. While the effects of age on the transmission of the chemical signal has been extensively studied, we know little on how time alters neuronal intrinsic excitability. This is critical as the modulation of intrinsic excitability is a key mechanism that controls the capability of neurons to undergo synaptic plasticity and thereby memory formation. Today, we know that cellular mechanisms that regulate neuronal excitability are not static, but are continuously subjected to an ever-changing physiological milieu, such as age-driven changes of key proteins involved in memory processes. Identifying such molecular targets of aging, their associated cellular functions, and examining how they contribute to learning and memory is key to our understanding of the mechanisms by which time affects the building blocks of cognitive functions. The sigma-1 receptor (s1) is an enigmatic protein involved in both the regulation of intrinsic excitability, i.e., the ability of a neuron to generate the electrical signal, and learning and memory. Interestingly, the beneficial effect of s1 activation on memory is more pronounced in aged individuals compared to young. An intriguing underlying candidate mechanism is the differential ability of s1 to regulate neuronal intrinsic excitability through time.  LONG-TERM GOAL: To identify and examine fundamental cellular mechanisms regulating neuronal intrinsic excitability, synaptic plasticity, and how these mechanisms contribute to memory formation. To this end, we combine approaches ranging from molecular, cellular, to behavioral analyses. SHORT- AND LONG-TERM objectives: To examine pro-plasticity and promnesic properties of s1, aiming to gain mechanistic insights into the role of s1 in these processes across the whole lifespan. 1. Determine the impact of s1 activity on neuronal intrinsic excitability and synaptic plasticity as a function of age. 2. Determine the relationships between s1 activity and learning and memory as a function of age. 3. Elucidate cellular mechanisms by which s1 regulates neuronal intrinsic excitability. 4. Establish causality between s1-driven changes in neuronal firing, synaptic plasticity, and learning and memory.  CONCLUSION: The power of our studies ultimately lies in their ability to provide a multipronged approach on the role of s1 in the regulation of neuronal intrinsic excitability, and how this function impacts synaptic plasticity and learning abilities through time, which is relevant to a specialized and broad neuroscience audience.