Matthew Anderson Laboratory


MAndersonMatthew P. Anderson, MD, PhD, is an Associate Professor and Principal Investigator in the Departments of Pathology and Neurology and Director of Neuropathology at Beth Israel Deaconess Medical Center, an affiliate of Harvard Medical School. The Anderson Laboratory studies the molecular, cellular and neural network mechanisms responsible for disorders of membrane excitability and synaptic transmission in the central nervous system. 

My prior studies, while training as a PhD student with Dr. Michael J. Welsh, HHMI Investigator, determined the function and regulation of the gene mutated in the lethal genetic disease cystic fibrosis. The work established the cystic fibrosis gene product, CFTR, encodes the epithelial apical membrane chloride channel essential for trans-epithelial ion and fluid secretion. Evidence that CFTR encodes the chloride channel pore was provided when CFTR cDNA induced chloride channels in diverse cell types in vitro (Anderson et al., Science, 1991a). More importantly, mutations of amino acids in the transmembrane domain altered channel pore properties (Anderson et al., Science, 1991b). 

We also established that CFTR displays novel channel regulation by intracellular, hydrolysable, nucleoside triphosphates through the nucleotide binding domains (Anderson et al., Cell, 1991). The result clarified the enigma that CFTR is not a member of known ion channel families, but instead homolog of ATP hydrolyzing membrane transporter proteins (pumps) that actively transport ions and other metabolites. The results suggest CFTR crossed the boundary between active pumps and passive ion channels during evolution. More importantly, the results identified the function of the cystic fibrosis gene product, and explained how mutations found in cystic fibrosis patients cause disease (Anderson et al., Science, 1992). 

While training as a postdoctoral fellow with Nobel Laureate and HHMI Investigator Susumu Tonegawa at MIT, I focused on the ion channels in the CNS that mediates burst firing which is prominent in the thalamus during chronic pain, sleep, and epilepsy. I used Cre/loxP-based conditional mouse genetics to identify a novel inherited form of insomnia (an arousal disorder) produced when T-type Ca2+ channel Cav3.1 is mutated. I invented methods for selective gene manipulations in the thalamus using Cre/loxP and BAC recombineering of the thalamus-enriched Kv3.2 promoter, now available a JAXS lab (Tg(Kcnc2-cre)K128Stl; Anderson et al., PNAS, 2005). I also used embryonic stem cell homologous recombination to create a new conditional knockout allele (loxP-flanked) of Cav3.1 gene that is selectively deleted in those cells expressing Cre recombinase. I then crossed the thalamic Cre and another cortical Cre transgenic line to the floxedCav3.1 line to selectively delete exons critical to expression of functional Cav3.1 T-type Ca2+ channels either in thalamic relay neurons or in cortical pyramidal neurons. Thalamic, but not cortical deletion of Cav3.1 caused a sleep disorder characterized by delayed sleep initiation and frequent arousals from sleep. Furthermore, I used an acute brain slice preparation and whole-cell, patch-clamp electrophysiology techniques to identify that Cav3.1 deletion causes defective inhibition of thalamic relay neuron firing. In aggregate, the studies identified a brain region and cellular mechanism underlying a novel mammalian sleep disorder (Anderson et al., PNAS, 2005).

Current efforts focus on cellular and neural network mechanisms responsible for genetic human epilepsy and autism disorders. Either human disease gene mutations or gene copy number variations that model these disorders are reconstituted using molecular genetics techniques in the mouse. In some cases, the mutated genes are targeted for expression or deletion in specific brain regions or cell-types to map the seizure or behavioral disorder loci. These novel human disease models are investigated using patch-clamp electrophysiology for defects in circuit function, biochemistry for defects in signaling, in vivo electrophysiology for epilepsy, and behavior analysis for defects characteristic of autism spectrum disorder (impaired communication and social interaction, and repetitive stereotypic behavior). Our goal is to understand the pathophysiological mechanisms of these two major neurological diseases. Using these techniques, we discovered that the human epilepsy gene, LGI1, is mutated to arrest postnatal development of glutamatergic circuits (Zhou et al. Nature Medicine, 2009; NINDS R01NS057444-01). This is the first human gene mutation that acts to arrest childhood brain development (Epilepsy: Synapses stuck in childhood. News and Views, Nature Medicine, 2009).

Diverse genetic defects, immunological insults, and certain epilepsies are implicated in the pathophysiology of autism spectrum disorder (ASD). Our research program combines a range of conditional genetic mouse models, genome-wide transcriptional profiling, protein interaction network analysis, conditional viral vectors, in vivo chemogenetics, and slice optogenetic electrophysiology techniques with extensive behavioral analysis to demonstrate a point of molecular convergence within an autism gene network that may explain social impairments in patients with certain forms of autism (e.g. maternal 15q11-13 triplications) and epilepsy. We believe these experimental approaches will set new standards for the study of molecular and circuit level dysfunction in mouse models of autism and other neurobehavioral disorders, and is the first to demonstrate a molecular mechanism that may underlie gene x seizure interactions that can impact social behavior in certain genetic disorders with epilepsy.

15q11-13 triplications cause a highly penetrant autism linked to increased UBE3A dosages (Smith et al. Science Translational Medicine 2011), a ubiquitin-ligase and transcriptional co-regulator. Nuclear-confined increases of UBE3A impair sociability by repressing Cbln1 gene expression, a key node in an autism gene network of protein-protein interactions that trans-synaptically binds NRXN and GRID, two gene families frequently deleted in autism. Separately, epileptic seizures (causing activity-dependent Cbln1 repression) synergize with Ube3a to impair sociability and do so through Ube3a-dependent mechanisms in glutamatergic neurons of the ventral tegmental area (VTA). Thus we show that experiencing seizures can uncover the effects of hidden asymptomatic gene mutations that make them prone to seizure-induced autism-related difficulties with social interaction.

Our working model is that many of the distinct behavioral and neurological problems in ASD arise from neuronal circuits in distinct parts of the brain. For example, we mapped the impaired sociability to midbrain ventral tegmental area. The deficit in sociability, we show arises from UBE3A and seizure-induced repression of the gene encoding synapse organizer CBLN1. A deficit reversible in the adult using preclinical AAV viral vector gene therapy (Krishnan et al. Nature 2017).