Extracellular calcium and thalamic discharge

Effects on EEG rhythms are seen in many pathological states primarily involving calcium metabolism, such as hyperparathyroidism and vitamin D poisoning, or in other conditions in which the extracellular calcium concentration [Ca2+]o is secondarily influenced, such as malignancies, renal failure, and some disorders of the endocrine system. During persistent hypercalcaemia, various neuropsychiatric symptoms can be present, including a state ranging from drowsiness to lethargy, and there is low frequency electroencephalographic (EEG) activity.
In vivo experiments from our laboratory showed that intraventricular CaCl2 injections in freely moving adult rats tripled the EEG amplitude and increased the relative power of the low EEG frequencies, with a decrease of the fast activity confirming the primary involvement of calcium ions in central nervous system functional alterations.

The thalamic neurons play an important role in the electro-cortical rhythms. They fire with single spikes during wakefulness (relay mode), and oscillate and synchronise their firing, producing bursts of action potentials, during slow-wave sleep (oscillatory mode). The rhythms arise as a consequence of the intrinsic pacemaker property of the neurons and the network of excitatory and inhibitory synaptic connections within the thalamus and between the thalamus and the cortex.
The crucial parameter controlling the transition from relay mode to oscillatory mode and viceversa is the resting membrane potential of the thalamo-cortical neurons.
Our research show that increasing the extracellular calcium concentration [Ca2+]o alone induced a transition of the discharge from single spike to burst mode in isolated current-clamped neurons and
These findings shed light on the correlation between hypercalcaemia, low frequency EEG activity and symptoms such as sleepiness and lethargy described in many clinical papers.

On the other hand, it is known that at low [Ca2+]o seizures are sometimes observed from different structures in the brain. Seizures are also induced by an increase in extracellular [K+] or other agents that can also induce depolarisation. Interestingly enough, many anti-epileptic drugs have hyperpolarizing effects, and can induce drowsiness.

Changes of [K+]csf and/or [Ca2+]csf altering the membrane potential can modify the thalamo-cortical firing. It is suggested that whereas the hyperpolarizing effects lead to neuronal burst discharge and EEG synchronisation, the depolarising effects of low [Ca2+](csf) or an increase in [K+](csf), lead to a lower frequency pathological burst discharge and epileptic seizures. This latter activity, at least in some cases, may involve enhanced Na+ influx through INa,P (Li & Hatton, 1996) rather than LVA Ca2+ currents that, in turn, cause neuronal burst discharge during SWS-EEG synchronisation. In addition, the reduction in [Ca2+]csf that may occur during paroxysmal neuronal activity can act as a positive feedback, activating a Ca2+-sensitive depolarising current, leading to further depolarisation and hyper excitability. (Formenti et al. 2001).

FORMENTI, A., ARRIGONI, E., MARTINA, M., TAVERNA, S., AVANZINI,G. & MANCIA, M. (1995). Calcium influx in rat thalamic relay neurons through voltage-dependent calcium channels is inhibited by enkephalin. Neuroscience Letters 201, 21–24.

FORMENTI, A., ARRIGONI, E. & MANCIA, M. (1996). Effects on the electroencephalogram induced by the changes in cerebrospinalfluid Ca2+-concentration: cellular mechanisms. Society for Neuroscience Abstracts 22, 64.16.