Mechanisms Of Synaptic Plasticity In The Adult And Developing Nervous System

National Institute Of Environmental Health Sciences

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Abstract

A longstanding issue in environmental health is the need to understand the role the environment plays in human brain development. The brain of the neonate is particularly susceptible to disruption of the sensory environment, which can have profound effects on its physiology and morphology. Such susceptibility of the developing brain to environmental influence by sensory manipulation or to environmental toxicants is particularly pronounced during defined critical periods of postnatal life. On the one hand, this susceptibility makes the developing brain particularly vulnerable to toxic insults. On the other hand, the plasticity of the connections between neurons, or synapses, is critical for refining brain circuitry during postnatal development. Similar mechanisms for changing synapses are likely to serve the basis for learning in the adult. Our primary interest, therefore, has been to determine the molecular basis of long-lasting synaptic plasticity. Toward our goal of learning how neuronal activity can induce lasting modifications in neurons, we use a diverse collection of molecular, biochemical, electrophysiological, and imaging techniques. We use the hippocampal slice preparation from neonate and adult mice. The relatively simple laminar structure of the hippocampus, which itself plays an important role in learning and memory, allows electrophysiological studies to be performed easily. To measure synaptic plasticity, we use techniques that include whole-cell patch clamp recordings from hippocampal slices maintained in vitro, and stimulate them either electrically or pharmacologically to induce long-term potentiation (LTP) or long-term depression (LTD). To determine how transcription is regulated in different hippocampal subfields, we use molecular and biochemical methods with tissue harvested by laser capture microdissection (LCM). In addition, we now use in vivo recording and tracing techniques to address the role of the different hippocampal subregions in specific behaviors. One approach that we have taken to gain insight into the mechanisms of regulating synaptic plasticity has been to compare highly plastic brain areas, such as the CA1 area of hippocampus, with less plastic areas. From the expression pattern of some genes, we predicted and found that one area of the hippocampus, the CA2, would have a resistance to synaptic plasticity including LTP and LTD, even though we found that synaptic responses in CA2 were very similar to those in the neighboring CA1 and CA3 areas. We later established that dendritic spines in CA2 have very different calcium dynamics from spines in CA1 and CA3 in that both calcium buffering capacity and rates of calcium extrusion were higher in CA2 spines when compared with those in the neighboring regions. In addition, we have found that a regulator of G-protein signaling (RGS-14), and adenosine A1 receptors (A1Rs), which are highly enriched in CA2, are also negative regulators of plasticity in CA2. We have also found that the social neuropeptides oxytocin and vasopressin act to induce synaptic potentiation in CA2 pyramidal neurons in a way that closely resembled typical LTP. The vasopressin 1b receptor (avpr1b) is highly enriched in CA2 neurons over all other parts of the brain, suggesting that CA2 may play an important role in social behavior; recent work in other laboratories support this view. To gain further insight into the molecular profile of CA2 neurons, we used RNAseq to measure mRNA from specific cellular compartments of tissue isolated by LCM. These studies have revealed that CA2 neurons express an unusually large number of genes related to mitochondrial function. Using the information we have gained from studying CA2, we also aim to determine the nature of the developmental down-regulation of synaptic plasticity in the form of critical periods and how plasticity is modulated in different brain areas. Recently, we have found that a specialized extracellular matrix, called perineuronal nets (PNNs), play a role in limiting synaptic plasticity in area CA2. We found that in mouse CA2, PNNs surround pyramidal (excitatory) neurons and their excitatory synapses on dendritic spines. Importantly, we found that staining for PNNs increases during postnatal development and could be modified by early-life enrichment. Because PNNs had been previously implicated in limiting synaptic plasticity late in postnatal development, effectively ending critical periods for plasticity, we tested whether PNNs also play an important role in restricting synaptic potentiation of the normally plasticity-resistant excitatory CA2 synapses. We found that treatment of hippocampal slices with an enzyme that disrupts PNNs enables synaptic potentiation in CA2 pyramidal neurons. CA2 and its surrounding regions are anatomically and molecularly very similar, and as such, these findings may therefore lead to identification of other critical molecular components in the pathways necessary for developmental changes in synaptic plasticity and development of normal cognition. Prior to our work on synaptic plasticity in area CA2, few groups had appreciated that the area was in fact a distinct region of the hippocampus and as a result, nothing was known about the how neurons in area CA2 function during even the simplest of behaviors such as exploration of an open field. We therefore recorded neuronal activity of CA2 neurons in vivo in rats during exploration and social interactions and found that CA2 neurons are uniquely sensitive to changes in social context and other situations involving novelty, suggesting that neurons in this area may be providing downstream regions with information relevant to changes in context. We next sought to determine how CA2 activity may regulate hippocampal electrical oscillations, which arise from coordinated activity among distinct populations of neurons and are associated with cognitive functions. Using the controlled experimental system of excitatory and inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate CA2 neuronal activity in mice, we studied hippocampal-prefrontal cortical network oscillations. We found that modification of CA2 activity increased or decreased hippocampal and prefrontal cortical low-gamma oscillations with excitatory and inhibitory DREADDs, respectively, and that CA2 activity inversely modulated hippocampal ripple oscillations. These findings support a role for CA2 in low-gamma generation and ripple modulation within the hippocampus and underscore the importance of CA2 in extrahippocampal oscillations. As increasing evidence is implicating area CA2 in several types of rodent social behavior, including aggression, these findings have relevance to human psychiatric disorders such as autism and schizophrenia that manifest with deficits in social cognition. Together with our studies on the cellular mechanisms underlying synaptic plasticity, these studies will give us a better understanding of how experience during development shapes brain circuitry.