Tracy S. Gertler

Dichotomous Anatomical Properties of Adult Striatal Medium Spiny Neurons

Principal medium spiny projection neurons (MSNs) of the striatum have long been thought to be homogeneous in their somatodendritic morphology and physiology. Recent work using transgenic mice, in which the two major classes of MSN are labeled, has challenged this assumption. To explore the basis for this difference, D1 and D2 receptor-expressing MSNs (D1 and D2 MSNs) in brain slices from adult transgenic mice were characterized electrophysiologically and anatomically. These studies revealed that D1 MSNs were less excitable than D2 MSNs over a broad range of developmental time points. Although M1 muscarinic receptor signaling was a factor, it was not sufficient to explain the dichotomy between D1 and D2 MSNs. Reconstructions of biocytin-filled MSNs revealed that the physiological divergence was paralleled by a divergence in total dendritic area. Experimentally grounded simulations suggested that the dichotomy in MSN dendritic area was a major contributor to the dichotomy in electrophysiological properties. Thus, rather than being an intrinsically homogenous population, striatal MSNs have dichotomous somatodendritic properties that mirror differences in their network connections and biochemistry.

Control of Cognition and Adaptive Behavior by the GLP/G9a Epigenetic Suppressor Complex

The genetic basis of cognition and behavioral adaptation to the environment remains poorly understood. Here we demonstrate that the histone methyltransferase complex GLP/G9a controls cognition and adaptive responses in a region-specific fashion in the adult brain. Using conditional mutagenesis in mice, we show that postnatal, neuron-specific deficiency of GLP/G9a leads to derepression of numerous nonneuronal and neuron progenitor genes in adult neurons. This transcriptional alteration is associated with complex behavioral abnormalities, including defects in learning, motivation, and environmental adaptation. The behavioral changes triggered by GLP/G9a deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with structural alterations of the GLP/EHMT1 gene. The likely causal role of GLP/G9a in mental retardation in mice and humans suggests a key role for the GLP/G9a-controlled histone H3K9 dimethylation in regulation of brain function through maintenance of the transcriptional homeostasis in adult neurons.

Calcium homeostasis, selective vulnerability and Parkinson's disease

Parkinsons disease (PD) is a common neurodegenerative disorder of which the core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Recent work has revealed that the engagement of L-type Ca(2+) channels during autonomous pacemaking renders SNc DA neurons susceptible to mitochondrial toxins used to create animal models of PD, indicating that homeostatic Ca(2+) stress could be a determinant of their selective vulnerability. This view is buttressed by the central role of mitochondria and the endoplasmic reticulum (linchpins of current theories about the origins of PD) in Ca(2+) homeostasis. Here, we summarize this evidence and suggest the dual roles had by these organelles could compromise their function, leading to accelerated aging of SNc DA neurons, particularly in the face of genetic or environmental stress. We conclude with a discussion of potential therapeutic strategies for slowing the progression of PD.

HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease

Parkinsons disease is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined for the generation of pacemaking. After the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking, which normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that is essential in pacemaking, the hyperpolarization and cyclic nucleotide–gated (HCN) channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, rather than a cause, of key network pathophysiology, a conclusion that is consistent with the ability of L-type channel antagonists to attenuate silencing after DA depletion.

A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease

Parkinsons disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L‐type Ca2+ channels with a pore‐forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L‐type Ca2+ channel independent mechanism to generate autonomous activity. This “rejuvenation” confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades‐long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD.

The role of dopamine in modulating the structure and function of striatal circuits

Dopamine (DA) is a key regulator of action selection and associative learning. The striatum has long been thought to be a major locus of DA action in this process. Although all striatal cell types express G protein-coupled receptors for DA, the effects of DA on principal medium spiny neurons (MSNs) understandably have received the most attention. In the two principal classes of MSN, DA receptor expression diverges, with striatonigral MSNs robustly expressing D(1) receptors and striatopallidal MSNs expressing D(2) receptors. In the last couple of years, our understanding of how these receptors and the intracellular signalling cascades that they couple to modulate dendritic physiology and synaptic plasticity has rapidly expanded, fuelled in large measure by the development of new optical and genetic tools. These tools also have enabled a rapid expansion of our understanding of the striatal adaptations in models of Parkinsons disease. This chapter highlights some of the major advances in these areas.

Strain-Specific Regulation of Striatal Phenotype in Drd2-eGFP BAC Transgenic Mice

Mice carrying bacterial artificial chromosome (BAC) transgenes have become important tools for neuroscientists, providing a powerful means of dissecting complex neural circuits in the brain. Recently, it was reported that one popular line of these mice—mice possessing a BAC transgene with a D2 dopamine receptor (Drd2) promoter construct coupled to an enhanced green fluorescent protein (eGFP) reporter—had abnormal striatal gene expression, physiology, and motor behavior. Unlike most of the work using BAC mice, this interesting study relied upon mice backcrossed on the outbred Swiss Webster (SW) strain that were homozygous for the Drd2-eGFP BAC transgene. The experiments reported here were conducted to determine whether mouse strain or zygosity was a factor in the reported abnormalities. As reported, SW mice were very sensitive to transgene expression. However, in more commonly used inbred strains of mice (C57BL/6, FVB/N) that were hemizygous for the transgene, the Drd2-eGFP BAC transgene did not alter striatal gene expression, physiology, or motor behavior. Thus, the use of inbred strains of mice that are hemizygous for the Drd2 BAC transgene provides a reliable tool for studying basal ganglia function.

Screening of conventional anticonvulsants in a genetic mouse model of epilepsy

Epilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may not be etiologically relevant for genetic epilepsies. Mutations in SCN1A are a common cause of Dravet Syndrome, a severe epileptic encephalopathy. Dravet syndrome typically begins in infancy with seizures provoked by fever and then progresses to include afebrile pleomorphic seizure types. Affected children respond poorly to available anticonvulsants. Scn1a+/− heterozygous knockout mice recapitulate features of Dravet syndrome and provide a potential screening platform to investigate novel therapeutics. In this study, we conducted a screening of conventional anticonvulsants in Scn1a+/− mice to establish assays that most closely correlate with human response data.

Imaging of Glutamate Concentration in Sturge-Weber Syndrome

Investigators from Wayne State University studied a cohort of children with Sturge-Weber syndrome (SWS) and epilepsy using both glucose-based positron emission tomography (FDG-PET) to evaluate metabolic activity and proton magnetic resonance spectroscopic imaging (MRSI) to evaluate glutamate turnover.

Prognosis with Incidental Rolandic Spikes

Investigators from Johns Hopkins University reported a cohort of 27 patients with incidentally-noted rolandic spikes (RS) on EEG.