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Commentary Neurons are endowed with the ability to dynamically regulate their ability to fire action potentials in response to alterations in overall network activity by changing the intrinsic excitability of their membranes and synapses (1). This adaptive process, termed homeostatic plasticity, is mediated in part by molecular signaling pathways that alter the phosphorylation of potassium ion channels, leading to changes in channel gating or clustering that alter ionic conductance in neuronal cell bodies, dendrites, or axons. Neurons can also adapt to changes in network activity by changing the number or properties of neurotransmitter receptors at afferent synapses. Yet, the role of homeostatic plasticity in abnormal conditions caused by excessive neuronal firing, such as epilepsy, is unclear. To determine whether homeostatic plasticity can compensate for decreases in neuronal inhibition seen in epilepsy, the authors examined mutant mice with homozygous deletion of the genes encoding the transcription factor Distal-less homeobox 1 (Dlx1) [2]. In these mice, spontaneous seizures appear in an age-dependent fashion, possibly due to apoptosis of cortical and hippocampal GABAergic interneurons following or concomitant with their migration from the medial ganglionic eminence (MGE), a germinal matrix in the embryonic ventral forebrain (3). In Dlx1mice, parvalbumin interneurons innervate the somatic regions normally, but there is a pronounced deficit in subsets of MGE-derived GABAergic interneurons expressing somatostatin, calretinin, or neuropeptide Y. These populations of interneurons target both excitatory and inhibitory interneurons. By adulthood, apoptosis of GABAergic interneurons results in a 50% reduction in synaptic inhibition in cortical circuits and reduced excitatory drive to hippocampal interneurons (4). In these mutant mice, there are deficits in both synaptic inhibition and synaptic excitation, and the question is whether homeostatic processes are involved. The authors explored this question by examining the neurochemical and electrophysiological properties of the transplanted cells and endogenous hippocampal neurons. Most of the transplanted interneurons expressed parvalbumin or somatostatin, and a smaller percentage expressed neuropeptide Y or calretinin. Remarkably, the transplanted cells eventually fired spontaneous action potentials and developed firing patterns characteristic of mature interneurons. Would these new interneurons form functional inhibitory synaptic connections with endogenous neurons in the epileptic mice? The researchers compared miniature inhibitory postsynaptic currents (mIPSCs) in Dlx1 and wild-type mice. This is a standard electrophysiological measure of the spontaneous release probability of synaptic vesicles containing GABA (5). mIPSC frequency was reduced in Dlx1 mice, as expected, and transplantation of GABAergic interneurons increased synaptic inhibition to levels comparable to wild-type mice. Several ways that neurons might compensate for decreased inhibitory drive include decreasing the strength of synaptic excitation or altering intrinsic membrane properties. To test for changes in synaptic excitation, the investigators recorded miniature excitatory postsynaptic currents (mEPSCs) from CA1 pyramidal cells. As with the trend for mIPSCs, the frequency of mEPSCs was decreased after interneuron loss and returned to Bidirectional Homeostatic Plasticity Induced by Interneuron Cell Death and Transplantation In Vivo.

The Art of Setting Limits: Lessons from GABAergic Interneuron Transplantation