Etranacogene dezaparvovec-drlb gene therapy for patients with hemophilia B (congenital factor IX deficiency).

Introduction: Congenital hemophilia B (HB) is an X-linked bleeding disorder resulting in Factor IX (FIX) deficiency and bleeding of variable severity. There is no cure for HB. Typical management consists of prophylactic intravenous (IV) recombinant or plasma-derived FIX infusions.

Overexpression of the autism candidate gene pathologically enhances olivo-cerebellar signaling in mice.

, the gene encoding cytoplasmic FMR1 interacting protein 1, has been of interest as an autism candidate gene for years. A potential role in autism spectrum disorder (ASD) is suggested by its location on human chromosome 15q11-13, an instable region that gives rise to a variety of copy number variations associated with syndromic autism. In addition, the CYFIP1 protein acts as a binding partner to Fragile X Messenger Ribonucleoprotein (FMRP) in the regulation of translation initiation.

Evaluating Gene Therapy as a Potential Paradigm Shift in Treating Severe Hemophilia.

Hemophilia is characterized by a deficiency in coagulation factors VIII or IX. The general standard of care for severe hemophilia is frequent intravenous recombinant or plasma-derived factor replacement to prevent bleeding. While this treatment is effective in preventing bleeding, frequent infusions are burdensome for patients.

Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism.

Background: Patients with autism spectrum disorder often show altered responses to sensory stimuli as well as motor deficits, including an impairment of delay eyeblink conditioning, which involves integration of sensory signals in the cerebellum. Here, we identify abnormalities in parallel fiber (PF) and climbing fiber (CF) signaling in the mouse cerebellar cortex that may contribute to these pathologies.

Methods: We used a mouse model for the human 15q11-13 duplication (patDp/+) and studied responses to sensory stimuli in Purkinje cells from awake mice using two-photon imaging of GCaMP6f signals.

Behavioral Tests for Mouse Models of Autism: An Argument for the Inclusion of Cerebellum-Controlled Motor Behaviors.

Mouse models of Autism Spectrum Disorder (ASD) have been interrogated using a variety of behavioral tests in order to understand the symptoms of ASD. However, the hallmark behaviors that are classically affected in ASD - deficits in social interaction and communication as well as the occurrence of repetitive behaviors - do not have direct murine equivalents. Thus, it is critical to identify the caveats that come with modeling a human disorder in mice.

Complex spike clusters and false-positive rejection in a cerebellar supervised learning rule.

Key Points: Spike doublets comprise ∼10% of in vivo complex spike events under spontaneous conditions and ∼20% (up to 50%) under evoked conditions. Under near-physiological slice conditions, single complex spikes do not induce parallel fibre long-term depression. Doublet stimulation is required to induce long-term depression with an optimal parallel-fibre to first-complex-spike timing interval of 150 ms.

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal.

At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes.

Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism.

A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behaviour and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behaviour deficits.

Enhanced AMPA receptor function promotes cerebellar long-term depression rather than potentiation.

Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites.