Spontaneous Correlated Activity in Developing Neural Circuits

Most current models of activity-dependent development assume that synaptic refinement is driven by neural activity that is correlated tightly in space (i.e., among neighboring cells) and in time (on the order of milliseconds) (Katz and Shatz 1996xKatz, L.C. and Shatz, C.J. Science. 1996; 274: 1133–1138Crossref | PubMed | Scopus (1922)See all ReferencesKatz and Shatz 1996). However, the spontaneous activity patterns described here have a periodicity on the order of minutes and spatial correlations among tens to hundreds of cells. The similarity in activity among these circuits raises the possibility that these broad temporal and spatial correlations may be important for guiding some aspects of circuit development.What sort of information might be encoded in the slow periodicity of spontaneous activity? In each of the three circuits, periodic bursts of action potentials lead to substantial increases in intracellular calcium concentration in the participating neurons. There is growing evidence that periodic changes in intracellular calcium occurring on the order of minutes can influence profoundly a variety of intracellular processes, including gene expression and the establishment of cell phenotype (Berridge 1998xBerridge, M.J. Neuron. 1998; 21: 13–26Abstract | Full Text | Full Text PDF | PubMed | Scopus (1402)See all ReferencesBerridge 1998). Indeed, in the developing spinal cord, the frequency of spontaneous calcium transients in growth cones regulates the rate of axon extension (Gomez and Spitzer 1999xGomez, T.M. and Spitzer, N.C. Nature. 1999; 397: 350–355Crossref | PubMed | Scopus (344)See all ReferencesGomez and Spitzer 1999). Hence, the periodicity of circuit activation may be tuned to the periodicity of intracellular signaling required to ensure normal maturation of neurons in either the rhythmic circuit itself or in its target tissue.This is not to argue that development of the retina, spinal cord, and hippocampus requires the same temporal information. In fact, the details of the spontaneous activity that are specific to each circuit may be relevant to the maturation of that circuit. For instance, in the case of the developing retina, at ages greater than P21, ON ganglion cells participate in only one-third of the waves that propagate through the OFF ganglion cells (Wong 1999xWong, R.O.L. Annu. Rev. Neurosci. 1999; 22: 29–47Crossref | PubMed | Scopus (337)See all ReferencesWong 1999). This difference in the periodicity might be critical in the establishment of the unique anatomical and functional specificity of these two classes of cells within the retina or the segregation of their inputs in the LGN.The spatial pattern of the activity can similarly encode important information. Synchronous activation of cells (e.g., hippocampus) contains no distinct spatial information regarding the relative positions of cells involved in each event, whereas propagating activity (e.g., retina and spinal cord) synchronizes the activity of subsets of cells, thereby encoding their relative positions. For instance, a single retinal wave will synchronize firing of cells along a wavefront with a particular orientation on the retina, generating an activity pattern that might be used to establish orientation selectivity in visual cortical neurons (reviewed by Miller 1994xMiller, K.D. Prog. Brain Res. 1994; 102: 303–318Crossref | PubMedSee all ReferencesMiller 1994). Activity patterns averaged over a large number of waves would lose orientation information but would maintain highly correlated firing among neighboring neurons, information that might be used in the establishment of topographic projections.Whether mechanisms that process activity correlated across large numbers of neurons exist in the developing brain and whether these correlations are critical for the normal formation of adult circuits remains to be determined. The search is on for pharmacological and genetic manipulations that change the frequency at which rhythmic events occur, significantly alter the distance over which cells are correlated, or transform the activity into uncorrelated firing of neurons. If found, these manipulations could be used in vivo to determine directly which aspects of patterned spontaneous activity are relevant to neural development.*E-mail: marla@codon.nih.gov.