Aberrant Dendritic Excitability: A Common Pathophysiology in CNS Disorders Affecting Memory?

Abstract

Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. (Need to distinguish between pure genetic forms which are rare, and what most people get which is probable combination of genetic susceptibility and environmental insults). Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS diseases may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher-order circuit and network abnormalities observed in CNS diseases, and their subsequent affect on memory.

Synaptic tagging during memory allocation

“…Considering the fundamental evolutionary importance of recalling the right set of memories at a critical time, we suspect that there are many mechanisms of memory allocation, including multiple strategies to shape the excitability of neurons after memory formation. Indeed, abnormalities in mechanisms that affect neuronal excitability are thought to contribute to a range of cognitive disorders 39 .…”

“…These decreases in excitability may also lead to deficits in memory allocation; specifically, memories that would otherwise be linked and stored together or memories that might strengthen each other are unable to do so because of the lower excitability levels of the aged brain. Importantly, abnormalities in mechanisms that affect neuronal excitability are thought to contribute to a range of cognitive disorders 39 . For example, it is possible that changes in neuronal excitability and associated deficits in memory allocation could lead to inappropriate connections between memories and therefore contribute to the frequent loose association of thoughts or speech that is seen in schizophrenia.…”

Tsc1 haploinsufficiency is sufficient to increase dendritic patterning and Filamin A levels

“…Alterations in dendritic patterning have not been observed in hippocampal neurons of Tsc1 +/− mice in vivo [13]. This is somehow surprising considering that dendritic defects are often observed in disorders associated with cognitive or psychiatric deficits [14–17] and are a classical outcome of increased mTORC1 or ERK activity (see [9;18] for additional references). Because, the defects in axonal patterning were modest, it is possible that a modest defect in dendritic patterning may not be detectable by analyzing the number of first and second dendrites as performed in the published study using Tsc1 +/− mice [13].…”

MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR

“…As such, alterations in dendritic morphology affect network activity and stability (Hausser et al, 2000; Jan and Jan, 2010; Sjostrom et al, 2008). Anomalies in dendritic morphology are observed in and contribute to the pathology of many neurodevelopmental and neurodegenerative disorders (Dierssen and Ramakers, 2006; Jan and Jan, 2010; Nestor and Hoffman, 2012). In particular, abnormal dendritic complexity is a shared feature of neurodevelopmental disorders associated with cognitive and social impairments, and altered TSC-mTOR signaling (Crino et al, 2006; Feliciano et al, 2013a; Kwiatkowski and Manning, 2005; Kwon et al, 2006).…”