No abstract

SUMMARY1. Experiments using intracellular recording techniques were performed on rat hippocampal neurones in vitro, to study the discharge properties of these cells.2. When CA 1 pyramidal cells were excited by injecting long depolarizing current pulses (approximately 600-800 ms), they responded with an initial rapid action potential discharge which slowed, or accommodated, and then stopped after 200-300 ms. The train of action potentials was followed by a hyperpolarization which was due primarily to calcium-activated potassium conductance (GK(Ca)). The amplitude of this hyperpolarization increased with an increasing number of action potentials in the initial discharge.3. Blocking the calcium-activated potassium conductance, by injecting EGTA into the cell, by bathing the cell in cadmium, a calcium channel blocker, or by bathing the cell in calcium-free medium, reduced the after-hyperpolarization (a.h.p.) and accommodation such that the frequency of action potential discharge increased and the duration of this discharge was prolonged. Blocking the calcium-activated potassium conductance had a greater effect on discharge frequency later in the action potential train, as late interspike intervals were shortened more than early ones by the application of cadmium or of calcium-free medium. This was presumably because the calcium-activated potassium conductance was more developed later in the train.4. Accommodation was not completely abolished in the absence of calcium and presence of cadmium, suggesting that other factors, in addition to calcium-activated potassium conductance, contributed to this process. This remaining accommodation was reduced by low doses of carbachol, suggesting that the M-current also plays a role in accommodation.5. We conclude that accommodation of the action potential discharge of hippocampal pyramidal cells may be regulated by at least two potassium currents: the calcium-activated potassium current and the M-current. Both of these currents are turned on during excitation of the neurone and act in an inhibitory manner on that neurone to limit further action potential discharge.

Long-term potentiation (LTP) of synaptic transmission is a widely studied model of neuronal plasticity. The induction of LTP is known to require processes in the postsynaptic neuron, while experimental evidence suggests that the expression of LTP may occur in the presynaptic terminal. This has led to speculation that a retrograde messenger travels from the post- to the presynaptic cell during induction of LTP. Extracellular application or postsynaptic injection of two inhibitors of nitric oxide synthase, N-nitro-L-arginine or NG-methyl-L-arginine, blocks LTP. Extracellular application of hemoglobin, which binds nitric oxide, also attenuates LTP. These findings suggest that nitric oxide liberated from postsynaptic neurons may travel back to presynaptic terminals to cause LTP expression.

The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement-and synapse elimination-independent role for C1q in CNS aging.

A slow muscarinic EPSP, accompanied by an increase in membrane input resistance, can be elicited in hippocampal CA1 pyramidal cells in vitro by electrical stimulation of cholinergic afferents in the slice preparation. Associated with the slow EPSP is a blockade of calcium-activated potassium afterhyperpolarizations (AHPs) (Cole and Nicoll, 1984a). In this study a single-electrode voltage clamp was used to examine the currents affected by activation of muscarinic receptors, using either bath application of carbachol or electrical stimulation of the cholinergic afferents. The 3 main findings of this study are that (1) of the 2 calcium-activated potassium currents (termed IAHP and IC) in hippocampal pyramidal cells, only IAHP is sensitive to carbachol; (2) IAHP is approximately 10-fold more sensitive to carbachol than is another muscarine-sensitive current, IM; and (3) neither blockade of IAHP nor of IM can account for the production of the slow EPSP. Rather, the slow EPSP appears to be generated by the blockade of a nonvoltage-dependent, resting potassium current. We propose that the muscarinic blockade of IAHP, which largely accounts for spike frequency adaptation, is primarily involved in enhancing action potential discharge to depolarizing stimuli, while the slow EPSP acts directly to cause action potential discharge.