Enhanced Excitability In Immature Brain

The immature brain is especially susceptible to seizures (43,44). Seizure incidence is highest during the first decade and especially during the first year of life. Several physiologic features favor enhanced neuronal hyperexcitability early in life. Ca2+ and Na+ channels, which mediate neuronal excitation, develop relatively early. Excitatory synapses tend to form before inhibitory ones. Excitatory NMDA receptors are transiently overexpressed early in postnatal development, when they are needed for critical developmental processes. The branching pattern of axons in the immature brain is markedly more complex than later in life, forming an exuberant network of excitatory connections (45). The ability of glial cells to clear extracellular K+ also improves with age.

GABA, perhaps paradoxically, exerts an excitatory action early in development, rather than the inhibitory effect seen later (46). Early in development, chloride ion (Cl-) concentration is greater inside the neuron than outside, and the reversal potential for Cl-is close to action potential threshold. Therefore, early in development, when GABA binds to its receptors and opens Cl- channels, the negatively charged chloride ions inside the neuron flow to the outside, down their electrochemical gradient. The loss of negative charge from inside the neuron depolarizes it to a membrane potential closer to the threshold for an action potential (Fig. 8). Later in development, the opposite situation occurs: Cl+ predominates in the extracellular space as a result of the expression of a membrane protein called KCC2. KCC2 extrudes Cl-, keeping the basal Cl- concentration inside the neuron at about one quarter of its concentration early in life and the Cl-reversal potential is more negative than resting membrane potential (47,48). Therefore, in the mature brain, GABA receptor activation causes entry of Cl-, thus hyperpolarizing the neuron, keeping it further away from action potential threshold.

Therefore, for many reasons, the excitatory/inhibitory balance in the brain changes dramatically over the course of development. The disadvantage of these physiological adaptations is that the brain is especially vulnerable to hyperexcitability and seizure generation during a critical window of development. Nevertheless, these neurophysio-logical idiosyncrasies of early brain development also provide the opportunity for producing novel, age-specific therapies.

A Developing Brain: GABA is Depolarizing (excitatory)

Presynaptic Postsynaptic

Presynaptic Postsynaptic

B Mature Brain: GABA is Hyperpolarizing (inhibitory)

Fig. 8. Schematic diagram of the changes in GABA responsiveness over development. (A) In early development, activation of postsynaptic GABAa receptors causes efflux of Cl- ions because of the high intracellular Cl- concentration. This Cl- efflux causes membrane depolarization, because there is a net loss of negative charge from inside the neuron. (B) Later in development, the Cl- transporter KCC2 (not present early in development) reverses the Cl- gradient, such that the basal Cl- concentration is higher extracellularly. In this case, activation of GABAA receptors causes Cl- influx and hyper-polarization (net inward movement of negative charge), the usual function attributed to GABA.

Fig. 8. Schematic diagram of the changes in GABA responsiveness over development. (A) In early development, activation of postsynaptic GABAa receptors causes efflux of Cl- ions because of the high intracellular Cl- concentration. This Cl- efflux causes membrane depolarization, because there is a net loss of negative charge from inside the neuron. (B) Later in development, the Cl- transporter KCC2 (not present early in development) reverses the Cl- gradient, such that the basal Cl- concentration is higher extracellularly. In this case, activation of GABAA receptors causes Cl- influx and hyper-polarization (net inward movement of negative charge), the usual function attributed to GABA.

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