Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders?

Abstract

Altered dendritic spines are characteristic of traumatized or diseased brain. Two general categories of spine pathology can be distinguished: pathologies of distribution and pathologies of ultrastructure. Pathologies of spine distribution affect many spines along the dendrites of a neuron and include altered spine numbers, distorted spine shapes, and abnormal loci of spine origin on the neuron. Pathologies of spine ultrastructure involve distortion of subcellular organelles within dendritic spines. Spine distributions are altered on mature neurons following traumatic lesions, and in progressive neurodegeneration involving substantial neuronal loss such as in Alzheimer’s disease and in Creutzfeldt–Jakob disease. Similarly, spine distributions are altered in the developing brain following malnutrition, alcohol or toxin exposure, infection, and in a large number of genetic disorders that result in mental retardation, such as Down’s and fragile-X syndromes. An important question is whether altered dendritic spines are the intrinsic cause of the accompanying neurological disturbances. The data suggest that many categories of spine pathology may result not from intrinsic pathologies of the spiny neurons, but from a compensatory response of these neurons to the loss of excitatory input to dendritic spines. More detailed studies are needed to determine the cause of spine pathology in most disorders and relationship between spine pathology and cognitive deficits.

Introduction

The principal neurons of most brain regions are covered with small protrusions known as dendritic spines. Dendritic spines are the main sites of excitatory synaptic input for these neurons. Dendritic spine distribution and structure is altered in many diseases, including various forms of mental retardation. The similarity of spine pathology in many different diseases lead to the recent proposal that many types of mental retardation result from an common inability of spiny neurons to form normal spines [137]. A more generally applicable alternative may be that spine pathology is symptomatic of a loss of connectivity rather than a cause of it. To investigate these issues we review the common characteristics and causes of spine abnormalities in a large number of pathological conditions.

The pathology of dendritic spines is of general interest for several reasons. Spines appear to serve several different functions [113], [244], and observation of spine changes under the extreme conditions brought on by disease, injury, or experiment can help in understanding the relative importance of these functions. As principal sites of synaptic input spines play a key role in connectivity in the brain. Alterations in spine morphology that accompany disease are expected to have a significant impact on mental function. In addition, understanding spine plasticity in the extreme of pathological conditions will help elucidate the limits of normal synaptic plasticity during development, and during learning and memory in the mature brain.

Dendritic spines have received intense study in pathology because they are one of the few indicators of neuronal connectivity that can be seen with ordinary light microscopy [102]. However, only conditions far from normal physiological limits, that have dramatic effects on spine distribution, can be clearly identified in light microscopy. Likewise, only serious diseases resulting in deterioration of central nervous tissue, such as severe malnutrition or brain edema, generate sufficiently large changes in spine structure to be readily observed in conventional electron microscopy. Less extreme conditions, such as learning, electrical stimulation, anesthesia, acute intoxication, and aging, may lead to more subtle changes that go undetected in routine light and electron microscopy. For this reason, we do not discuss in detail many of these conditions nor do we consider experimental manipulations such as over-expression of particular proteins or animal genetic constructs, except where these are closely related to human neuropathology. Dramatic effects observed with reasonable descriptive methods are emphasized.

This review begins with a brief summary of normal dendritic spine anatomy and development to provide a context for assessing abnormalities. Typical spine pathologies are then summarized, followed by a limited review of specific diseases or conditions in which spine pathologies are commonly observed. Some of these data have been previously reviewed [238], [102], [124], [126], [137], [141].