Matthew 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). 

Recent studies, while training as a postdoctoral fellow with Nobel Laureate and HHMI Investigator Susumu Tonegawa at MIT, focused on the ion channels in the CNS that mediate 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 recently 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 (News and Views, Nature Medicine, 2009). 

We have also created a model of the human genetic epilepsy disorder associated with T-type Ca2+ channel Cav3.2 mutations (NINDS K02 NS054674) to assess whether inheritance of this mutant gene increases seizure susceptibility and circuit excitability. 

Two collaborative studies examine hypothalamic circuit adult neurogenesis and repair. These studies are collaborations between my lab and the laboratories of Dr. Jeffrey Flier and Dr. Jeffrey Mackliss with each lab contributing a unique and essential expertise. In both studies, my lab provides the electrophysiologic expertise, performing fluorescence-guided whole-cell, patch-clamp analyses of the firing properties and synapses of fluorescent adult newborn and progenitor transplanted neurons in hypothalamic brain slices. In the first study, an equal contribution between the Anderson and Flier lab, we evaluated whether neurogenesis continues to occur in the hypothalamus of the adult brain. Currently there are only two brain regions proven to continue to generate functional neurons in adulthood: the dentate gyrus (one neuronal subtype) and the olfactory bulb (two neuronal subtypes). Using retroviral (GFP) labeling of newly generated cells in the adult hypothalamus, we assess whether fully functional neurons are formed and incorporated in the adult hypothalamus. The second study evaluates whether transplanted progenitors can functionally incorporate into the adult hypothalamus to rescue obesity due to leptin receptor deficiency. 

My labs major focus and effort is now aimed at developing and investigating genetic and acquired mouse models of autism. We have developed and are characterizing a novel murine model of the most common human genetic autism spectrum disorder copy number variation, Idic15 (NINDS R21 ARRA Heterogeneity in Autism Disorder Grant 1R21NS070295-01). This will represent the first murine model of human autism disorder due to a gene copy number variation. We are currently developing multiple other models of human autism copy number variations using mouse molecular genetics. We are also investigating a novel acquired model of human autism where we assess whether immune system activity influences the normal postnatal development of neuronal circuits. 

Our goals are:

  • To identify the specific cell types and brain regions that are disrupted to produce epilepsy and autism
  • To define physiologic defects in these cells that underlie these disorders
  • To identify other candidate proteins responsible for these disorders
  • To identify potential targets for new therapies
  • Our studies investigate ion channels, transporters, T-type calcium channels, thalamus, cerebral cortex, hippocampus, inherited neurologic disease, inherited psychiatric disease, epilepsy, and autism
  • Our experimental methods include: embryonic stem cell homologous recombination, transgenic mice, GFP labeled neurons, Cre recombinase, Flp recombinase, BAC homologous recombination, lambda red recombinase, brain slice recording, current clamp, voltage clamp, patch-clamp electrophysiology, single channel recording, infrared guided whole-cell recording, cDNA cloning, siRNA, and region-restricted and conditional mouse genetics
  • Our team applies state-of-the-art experimental techniques to study these complex mechanisms. Our techniques include the production of genetically engineered mice to target inherited neurologic disease genes to specific neuronal or glial cell-types to identify the cellular locus of disease. We employ methods such as EEG and EMG recording to measure the behavioral disorders of epilepsy and sleep in mice. To measure defects in single neurons, including synaptic and firing properties, we use whole-cell, patch-clamp electrophysiology recording techniques in the acute brain slice from neonatal, juvenile, and adult mice. We are actively recording now from the thalamus, cortex, hippocampus, and amygdala.
Contact Information
Matthew P. Anderson, M.D., Ph.D.
Beth Israel Deaconess Medical Center
330 Brookline Avenue, E/CLS645
Boston, MA 02215
Cell: 781-710-1925
Office: 617-735-3202