Activity-dependent regulation of neuronal excitability in hippocampal neurons

Activity-induced modification of cellular properties is likely to be important for the development and the function of the nervous system. A great deal is known about the plasticity of excitatory glutamatergic synapses. In comparison, less is known about use-dependent modification of other determinants of neuronal excitability, such as GABAergic synaptic transmission and voltage-gated ion channels. GABA is an important regulator of neuronal excitability within the central nervous system. The effects of GABA receptor activation on neuronal firing are dependent on the reversal potential for GABA induced currents, which are set, in part, by the transmembrane ion gradient for chloride ions. During the early development of the nervous system, when most neurons maintain a high intracellular concentration of chloride, GABA is an excitatory neurotransmitter. Using a model system of dissociated rat hippocampal cultures, we find that the developmental change in GABA signaling from excitation to inhibition can be regulated by the level of GABAergic synaptic activity. GABA mediated excitation during the early development of the nervous system appears to triggers the expression of KCC2, a chloride cotransporter. We also find that the reversal potential for GABA can be modified by specific patterns of activity. Repetitive synchronous firing of a GABAergic presynaptic neuron and a given postsynaptic neuron, within a critical time window, can shift the reversal potential for GABAergic currents toward more depolarized values. In addition to GABAergic synaptic transmission, the intrinsic properties of neurons, as determined by the type and the properties of voltage-gated channels, are essential determinants of neuronal responses. We examined whether the intrinsic excitability of hippocampal neurons can be modulated. We found that repetitive correlated firing of excitatory glutamatergic synapses triggered a rapid and persistent enhancement of the presynaptic neuronal excitability, which required a temporal order between pre- and postsynaptic spiking and the activation of NMDA receptors. Correlated spiking appears to lower the threshold for spike initiation and modifies the sodium channel gating properties. These rapid activity-dependent changes in intrinsic neuronal properties may play a role in the development of the nervous system and the processing and storage of information.