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to predominate in the immature brain, with Nav1.6 becoming more prevalent during
maturation. Nav1.6 also carries a significant proportion of the persistent sodium current and
may play an important role in burst firing and ictogenesis.
Voltage-gated calcium channels
Voltage-gated calcium channels contribute to the overall electrical excitability of neurones,
are closely involved in neuronal burst firing, and are responsible for the control of
neurotransmitter release at pre-synaptic nerve terminals. Like sodium channels, voltage-gated
calcium channels comprise a single alpha-subunit, of which at least seven are known to be
expressed in mammalian brain. There are also accessory proteins, including beta- and alpha2-
delta-subunits, that modulate the function and cell-surface expression of the alpha-subunit
but which are not necessarily essential for basic channel functionality. Voltage-gated calcium
channels are commonly distinguished on the basis of their biophysical properties and patterns
of cellular expression. High-voltage-activated (HVA) channels respond to strong
depolarisations and are involved in both pre-synaptic neurotransmitter release (N-, P/Q-, and
R-type) and the processing of synaptic inputs at the somatodendritic level (L-type). In
contrast, the low-voltage-activated (LVA) channel opens in response to modest
depolarisations at or below resting membrane potential and gives rise to transient (T-type)
currents which participate in intrinsic oscillatory activity. The T-type channel is highly
expressed on the soma and dendrites of thalamic relay and reticular neurones where it has
been postulated to underpin the rhythmic 3 Hz spike-wave discharges that are characteristic
of absence seizures.
Voltage-gated potassium channels
Voltage-gated potassium channels are primarily responsible for repolarisation of the cell
membrane in the aftermath of action potential firing and also regulate the balance between
input and output in individual neurones. As a group, they are highly heterogeneous. More
than 40 voltage-gated potassium channel alpha-subunits have been identified thus far, each
of which is structurally similar to the alpha-subunits of voltage-gated sodium and calcium
channels. These are classified into 12 sub-families (Kv1 to Kv12), with individual channels
comprising four alpha-subunits from the same sub-family arranged around a central K+
sensitive pore, typically in a ‘two plus two’ conformation. Two functional classes of voltage-
gated potassium channel are well described in the literature. Kv1 to Kv4 channels are
expressed in dendrites, axons and nerve terminals and carry the delayed rectifier current (IK)
that repolarises the neuronal membrane after action potential firing. In contrast, Kv7 channels
are expressed in the cell soma and AIS and are responsible for the M-current, which
determines the threshold and rate of neuronal firing and modulates the somatic response to
dendritic inputs. Mutations in the KCNA1 gene, which encodes the Kv1.1 subunit, have been
implicated in episodic ataxia type 1, while mutations in KCNQ genes, which encode Kv7
channels, are responsible for benign familial neonatal convulsions.
Inhibitory neurotransmission
GABA is the predominant inhibitory neurotransmitter in the mammalian central nervous
system and is released at up to 40% of all synapses in the brain. GABA is synthesised from
glutamate by the action of the enzyme glutamic acid decarboxylase. Following release from
GABAergic nerve terminals, it acts on both GABAA and GABAB receptors, with a net
hyperpolarising or inhibitory effect. The GABAA receptor is a ligand-gated ion channel,
comprising five independent protein subunits arranged around a central anion pore permeable
to chloride and bicarbonate. Nineteen GABAA receptor subunits have been identified to date
(alpha16, beta13, gamma13, delta, epsilon, theta, pi, and rho13) which come together
as heteromeric pentamers to form functional channels. GABAA receptors mediating transient,
rapidly desensitising currents at the synapse (phasic receptors) typically comprise two alpha-,
two beta-, and one gamma-subunit, whereas those at extra-synaptic sites and mediating long-
lasting, slowly desensitising currents (tonic receptors) preferentially contain alpha4- and
