Hippocampal Area CA2
The hippocampus is required to form new declarative memories, but the contributions of area Cornu Ammonis 2 (or CA2) to hippocampal function are virtually unknown. Recent evidence indicates that CA2 may play an important role in mediating social memory and social aggression. Pyramidal neurons in area CA2 differ significantly from those in other hippocampal subfields, especially in regards to their morphological characteristics, afferent and efferent connectivity, intrinsic and synaptic properties, and gene and protein expression profiles. But perhaps one of the most notable characteristics of area CA2 is its resistance to multiple forms of activity-dependent synaptic plasticity. The ability to induce changes in synaptic efficacy in area CA2 differs dramatically from other hippocampal subfields in that Schaffer collateral inputs originating from area CA3 fail to support the induction of activity-dependent long-term potentiation (LTP) at synapses in CA2. Curiously, CA2 pyramidal neurons possess the intracellular machinery required to support induction of activity- and NMDA receptor-dependent LTP, but the high intrinsic calcium buffering and extrusion capacity of CA2 neurons normally prevents induction from occurring. Even more interesting is the observation that Schaffer collateral projections to CA2 are, indeed, quite plastic, but only in response to specific neuromodulatory signals (such as, adenosine or vasopressin). Multiple complimentary techniques are used in PlasticityLab to extend our limited knowledge and understanding of how such neuromodulatory signals can influence this relatively uncharacterised component of the hippocampal circuit.
Caffeine and Hippocampal Area CA2
Adenosine acts as a neuromodulator in the brain, and signalling at adenosine receptors in the hippocampus has been shown to influence memory formation and behaviour by regulating synaptic plasticity. Caffeine is a naturally-occurring cognitive enhancer that is widely-consumed to improve attention and augment memory. Its primary mechanism of action is thought to be through blockade of adenosine A1 receptors (A1Rs). Interestingly, A1Rs are highly expressed in pyramidal neurons in CA2 when compared to the rest of the hippocampal formation, and caffeine selectively enhances excitatory synaptic transmission in CA2 at concentrations that have little effect on responses evoked in other hippocampal subfields. Specifically, application of caffeine to hippocampal slices facilitates synaptic responses in Schaffer collateral inputs to area CA2, but not in the same inputs to CA1, nor in mossy fibre projections from the dentate gyrus to area CA3. This enhanced sensitivity to caffeine is related not only to the high expression of A1Rs in CA2, but also to an array of additional downstream signalling enzymes that are also highly enriched in CA2 neurons. In addition, two-photon confocal imaging of live CA2 pyramidal neurons in vitro has also shown that the A1R-mediated increase in synaptic efficacy is accompanied by a coincident change in the volume of spines located along branches of apical dendrites. Given the importance of experience-driven modifications in synaptic function to learning, memory and cognition, A1Rs in CA2 may play a significant role in mediating the cognitive-enhancing effects of caffeine. Understanding how caffeine and other neuromodulatory signals influence synaptic function in CA2 to modulate cognition and behaviour is a major focus of research in PlasticityLab.
Electrophysiological Properties of Cochlear Fibrocytes
Hearing loss is a global issue that affects nearly 360 million people. One form of age-related and metabolic hearing loss, known as presbycusis, is thought to result, in part, from the degeneration of a particular family of cells in the lateral wall of the cochlea known as fibrocytes. These cells are unique in that they are mesenchymal and have the capcity to regenerate. This property makes fibrocytes ideal targets for stem cell therapies to try and restore lost sensory function. Indeed, previous research has shown that stem cells injected directly into the cochlea migrate to the lateral wall and differentiate into fibrocyte-like cells. However, it is unclear whether these new cells possess all the functional characteristics required to support auditory transduction and restore hearing.
A new approach that we have been testing involves replacing dysfunctional fibrocytes with ones that have been custom-grown in the laboratory. These “ready-made” fibrocytes should integrate into the cochlea better than stem cells since they do not require significant differentiation or development. A critical first step, though, is to demonstrate that the cultured fibrocytes possess similar physiological properties as native fibrocytes. This confirmation will allow us to move forward and develop a novel cell replacement therapy that we can test in an animal model of age-related hearing loss (the CD1 mouse). This is a collaborative effort between Prof Dave Furness, Dr Mike Evans and myself at Keele University and we are currently funded by a research grant from Action on Hearing Loss to conduct this work.