By studying the visual system of mammals, the Shatz Lab discovered that adult wiring emerges from dynamic interactions between neurons involving neural function and synaptic plasticity. Even before birth and long before vision, the eye spontaneously generates and sends coordinated patterns of neural activity to the brain. Blocking this activity in utero, or preventing vision after birth, disrupts normal tuning up of circuits and brain wiring. In turn, neural activity regulates the expression of genes involved in the process of circuit tuning.
To discover cell and molecular underpinnings of circuit tuning, her lab has conducted functional screens for genes regulated by neural activity. Among these genes is the MHC (major histocompatibility) Class I family. This finding was very surprising because these genes- HLA genes in humans- are involved in cellular immunity and were previously not thought to be expressed by neurons at all! The Shatz Lab showed that other components of a signaling system for Class I MHC are also present in neurons, including a novel receptor, PirB.
By studying and/or generating knockout mice, the lab is exploring a role for these molecules in synaptic plasticity, learning, memory and neurological disorders. The lab employs a variety of approaches in these studies, ranging from molecular biology to slice electrophysiology to in vivo imaging to behavior. Research has relevance not only for understanding brain wiring and developmental disorders such as Autism and Schizophrenia, but also for understanding how the nervous and immune systems interact.
Requirement for Neural Activity in Visual System Development
When connections first form within a target structure, they are not established in the adult precise pattern. For example, connections between retina and its target nucleus in the thalamus, the lateral geniculate nucleus (LGN) are highly ordered with respect to eye input in the adult, such that ganglion cells from opposite eyes form connections within separate but adjacent eye-specific layers in the LGN. In contrast, in the fetus there are initially no layers: the ganglion cell inputs from the two eyes are intermixed and then gradually sort out to form the layers. Research in the laboratory demonstrated that the process of sorting requires neural activity. An important question currently under study is, how can neural activity “instruct” ganglion cell axons to sort into eye-specific layers?
Before we could answer this question, we had to determine the source of the neural activity. The eye-specific layers form even before the rods and cones are mature. Therefore vision cannot provide the signals. Using special techniques that allow us to monitor the activity of hundreds of neurons simultaneously, we discovered that even before rods and cones are present, retinal ganglion cells are spontaneously sending signals to the brain. These signals are highly coordinated such that neighboring cells signal at the same time, and a “wave” of activity sweeps across the eye periodically. The waves are generated by an early-functioning circuit within the retina that involves both the retinal ganglion cells and a special type of interneuron, the cholinergic amacrine cells. These periodic waves are present only during development when the layers are forming, and disappear just before eye opening. What is more, blocking these waves prevents the formation of the eye-specific layers in the LGN. Thus, the brain can supply its own activity early in development to help in the process of forming precise connections; later on, vision takes over.
Neurotrophins as Signaling Molecules in Activity-Dependent Development
The process of forming precise connections and eliminating imprecise ones during development involves not only short term changes in the strength of synaptic connections between the retinal ganglion cells and LGN neurons, but also long term structural changes in the branching patterns of ganglion cell axons. How is this long term change effected? One idea is that the target neuron releases a retrograde growth factor that is taken up by the presynaptic axon and acts to promote long term growth and stabilization of the input. We have been investigating this idea by studying the next set of connections in the visual pathway: from the LGN neurons to neurons of the primary visual cortex in the occipital lobe. In the adult, LGN axons representing each eye are segregated from each other in the primary visual cortex into columns (rather than into layers as in the LGN). Neural activity again is needed for columns to form, but during a later time in development when vision (rather than waves) provides the input.
For ganglion cell axons from each eye to sort into layers, LGN neurons must be able detect the the correlated firing of cells within one eye and strengthen those synapses that are coactive: “cells that fire together wire together”. By means of whole cell recording in slices of LGN in vitro, we demonstrated that the synaptic connections between ganglion cells and LGN neurons can undergo strengthening similar to Long Term Potentiation in the hippocampus when stimulated with the same firing patterns as those generated in vivo by the ganglion cells. We also discovered, in a special “reduced brain preparation”, that the spontaneous waves of activity generated in the eye are not only sent on to the LGN in the form of action potentials, but they are then relayed across synapses where they are powerful enough to make the LGN neurons fire action potentials.