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 (1) 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*1 activation on memory is more*pronounced in aged individuals compared to young. An intriguing underlying*candidate mechanism is the differential ability of 1 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 1, aiming to*gain mechanistic insights into the role of 1*in these processes across the whole